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WO2008067909A2 - Urea and sulfamide derivatives as tafia inhibitors - Google Patents

Urea and sulfamide derivatives as tafia inhibitors Download PDF

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Publication number
WO2008067909A2
WO2008067909A2 PCT/EP2007/010101 EP2007010101W WO2008067909A2 WO 2008067909 A2 WO2008067909 A2 WO 2008067909A2 EP 2007010101 W EP2007010101 W EP 2007010101W WO 2008067909 A2 WO2008067909 A2 WO 2008067909A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkylene
alkyl
phenyl
amino
unsubstituted
Prior art date
Application number
PCT/EP2007/010101
Other languages
German (de)
French (fr)
Other versions
WO2008067909A3 (en
Inventor
Christopher Kallus
Mark Broenstrup
Werngard Czechtizky
Andreas Evers
Markus Follmann
Nis Halland
Herman Schreuder
Original Assignee
Sanofi-Aventis
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to PL07856207T priority Critical patent/PL2104497T3/en
Priority to NZ577312A priority patent/NZ577312A/en
Priority to CA2671861A priority patent/CA2671861C/en
Priority to BRPI0720241-5A priority patent/BRPI0720241A2/en
Priority to EP07856207.1A priority patent/EP2104497B1/en
Priority to ES07856207.1T priority patent/ES2537093T3/en
Priority to SI200731653T priority patent/SI2104497T1/en
Priority to HK10103243.7A priority patent/HK1137928B/en
Priority to JP2009539631A priority patent/JP5396279B2/en
Priority to CN2007800435586A priority patent/CN101553219B/en
Priority to DK07856207.1T priority patent/DK2104497T3/en
Priority to AU2007327959A priority patent/AU2007327959B2/en
Application filed by Sanofi-Aventis filed Critical Sanofi-Aventis
Priority to HRP20150514TT priority patent/HRP20150514T1/en
Priority to MX2009005516A priority patent/MX2009005516A/en
Publication of WO2008067909A2 publication Critical patent/WO2008067909A2/en
Publication of WO2008067909A3 publication Critical patent/WO2008067909A3/en
Priority to ZA2009/03040A priority patent/ZA200903040B/en
Priority to US12/480,348 priority patent/US8389764B2/en
Priority to NO20092246A priority patent/NO20092246L/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
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    • A61K31/18—Sulfonamides
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    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
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    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the invention relates to novel compounds of the formula I which inhibit the enzyme TAFIA (activated thrombin-activatable fibrinolysis inhibitor), processes for their preparation and use thereof as medicaments.
  • TAFIA activated thrombin-activatable fibrinolysis inhibitor
  • the enzyme TAFIa is formed, for example, by thrombin activation from the thrombin-activatable fibrinolysis inhibitor zymogen (TAFI).
  • the enzyme TAFI is also referred to as plasma procarboxypeptidase B, procarboxypeptidase U or as procarboxypeptidase R and is a carboxypeptidase B like
  • thrombin is generated as the end product of the coagulation cascade and induces the conversion of soluble plasma fibrinogen to an insoluble fibrin matrix.
  • thrombin activates the endogenous fibrinolysis inhibitor TAFI.
  • TAFIa Activated fibrinolysis inhibitor
  • TAFIa cleaves basic amino acids at the carboxy end of fibrin. The loss of the carboxy-terminal lysines as binding sites for plasminogen then leads to an inhibition of fibrinolysis.
  • Effective inhibitors of TAFIa prevent the loss of these high-affinity lysine binding sites for plasminogen and thus support endogenous fibrinolysis by plasmin: TAFIa inhibitors act profibrinolytically.
  • the TAFIa inhibitors according to the invention are suitable for a prophylactic as well as for a therapeutic use in humans, which suffer from diseases that are associated with thromboses, embolisms, hypercoagulability or fibrotic changes. They can be used for secondary prevention and are suitable for both acute and long-term therapy.
  • the invention therefore relates to the use of the compound of the formula I.
  • R1 for 1) hydrogen atom, 2) - (C 1 -Ce) -Alkyl,
  • R 2 is the radical of the formula II - (A1) m -A 2 (II), where m is the integer zero or 1,
  • Ring system is understood with 4 to 15 ring atoms, which are present in one, two or three interconnected ring systems and the one, two, three or four identical or different heteroatoms from the
  • Alkyl, halogen, -NH 2, -CF 3 or -O-CF 3, 2) - (C 0 -C 6 ) -alkylene-NH 2 , 3) - (C 1 -C 6 ) -alkylene-NH-C ( NH) -NH 2 ,
  • NH 2 is substituted by -NH 2 and monosubstituted, disubstituted or trisubstituted by R 15, R 3 is 1) - (C 1 -C 6) -alkyl,
  • R4 is -N (R6) 2, wherein R6 are the same or different and independently of one another
  • Het is a 4- to 15-membered heterocyclic ring system is understood with 4 to 15 ring atoms, which are present in one, two or three interconnected ring systems and the one, two, contain three or four identical or different heteroatoms from the series oxygen, nitrogen or sulfur, wherein Het or alkylene is unsubstituted or independently of one another once, twice or three times by R11, halogen, -C (O) -O-RH, - (C ⁇ C 1 -C 4 ) -alkyl-O-R 11 or -O- (C 1 -C 4 ) -alkyl,
  • PG is a protective group for the amino, carboxyl or for the hydroxyl function
  • R 7 is hydrogen atom or - (C 1 -C 6) -alkyl
  • R 8 is hydrogen or - (C 1 -C 6) -alkyl
  • R 9 is hydrogen or - (C 1 -C ⁇ J -acyl
  • R11 and R12 are the same or different and independently of each other
  • R 13 is 1) hydrogen
  • R 14 is hydrogen, - (C 1 -C 4 ) -alkyl, -NH 2 or -OH
  • R 15 is hydrogen, - (C 1 -C 4 ) -alkyl, -O-CF 3 , -NH 2, -OH , -CF3 or halogen.
  • the invention also relates to the use of the compound of formula I wherein X is -C (O) -.
  • the invention also relates to the use of the compound of formula I, wherein X stands for -SO 2 -.
  • the invention also relates to the use of the compound of the formula I in which X is -C (O) -, R 1 is 1) hydrogen or 2) - (C 1 -C 4) -alkyl,
  • R 2 for 1) - (C 1 -C 6 ) -alkylene-NH 2 ,
  • R 3 is 1) - (C 1 -C 4 ) -alkyl, 2) - (C 0 -C 4 ) -alkylene- (C 3 -C 8) -cycloalkyl,
  • R4 is -N (R6) 2, wherein R6 are the same or different and independently of one another
  • R11 halogen, -C (O) -O-RH, - (C ⁇ C 4 ) -alkyl-O-R11 or -O- (C 1 -C 4 ) -alkyl,
  • Het is a 4- to 15-membered heterocyclic ring system is understood with 4 to 15 ring atoms, which are present in one, two or three interconnected ring systems and the one, two, contain three or four identical or different heteroatoms from the series oxygen, nitrogen or sulfur, wherein Het or alkylene is unsubstituted or independently of one another once, twice or three times by R11, halogen, -C (O) -O-RH, - (C ⁇ C 1 -C 4 ) -alkyl-O-R 11 or -O- (C 1 -C 4 ) -alkyl,
  • R 11 and R 12 are identical or different and independently of one another represent 1) hydrogen atom
  • R 13 is 1) hydrogen
  • R14 represents hydrogen atom, - (C 1 -C 4 -alkyl, -NH 2 or -OH, and
  • R 15 is hydrogen, - (C 1 -C 4 ) -alkyl, -O-CF 3 , -NH 2 , -OH, -CF 3 or
  • Halogen is available.
  • the invention also relates to the use of the compound of the formula I in which X is -C (O) -, R 1 is 1) hydrogen or 2) - (C 1 -C 4 ) -alkyl, R 2 is 1) - ( C 1 -C 6 ) -alkylene-NH 2 ,
  • R 3 is 1) - (C 1 -C 4) -alkyl
  • R4 is hydrogen
  • R4 is -N (R6) 2 , where R6 are the same or different and independently of one another
  • cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, bicyclo [3.1.1] heptanyl, decahydro -naphthalenyl, tetrahydronaphthalene, octahydro-4,7-methano-indenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently substituted once, twice, three or four times by - (C 1 -C 4 -alkyl , -C (O) -O-R11 or - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or substituted by halogen,
  • cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, bicyclo [3.1.1] heptanyl, decahydro-naphthalenyl, tetrahydronaphthalenyl, octahydro-4,7-methanoindenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently of one another mono-, di-, tri- or tetra-substituted by - (C-) C 1 -C 4) -alkyl, -C (O) -O-R 11 or
  • Isochromanyl isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolidinyl, 2-isothiazolinyl, isothiazolyl, isoxazolyl, isoxazolidinyl, 2-isoxazolinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1, 2,3-oxadiazolyl, 1, 2,4 -Oxadiazolyl, 1, 2,5-oxadiazolyl, 1, 3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, oxazolyl, oxazolidinyl,
  • Triazolyl 1, 2,3-triazolyl, 1, 2,4-triazolyl, 1, 2,5-triazolyl, 1, 3,4-triazolyl and xanthenyl, wherein Het or alkylene is unsubstituted or independently of one another or by - (C 1 -C 4) alkyl is substituted
  • alkyls are unsubstituted or independently of one another by halogen, phenyl, -C (O) -O-RH, - (C -
  • R7 is hydrogen atom or - (C-
  • R9 is hydrogen atom or - (C 1 -C 4 ) -alkyl
  • R11 and R12 are the same or different and independently of each other
  • cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, bicyclo [3.1.1] heptanyl, Octahydro-4,7-methanoindenyl or bicyclo [2.2.1] heptanyl and wherein cycloalkyl is unsubstituted or independent one, two, three or four times by - (C 1 -C 4) -alkyl,
  • R 13 is 1) hydrogen, 2) - (C 1 -C 4) -alkyl,
  • R 14 is hydrogen, - (C 1 -C 4 ) -alkyl, -NH 2 or -OH and R 15 is hydrogen, - (C 1 -C 4 ) -alkyl, -O-CF 3, -NH 2, -OH, -CF 3 or halogen.
  • the invention also relates to the use of the compound of the formula I in which X is -C (O) -, R 1 is 1) hydrogen or 2) - (C 1 -C 4) -alkyl,
  • R 2 for 1) - (C 1 -C 6 ) -alkylene-NH 2 ,
  • R 3 is 1 ) - (C 1 -C 4 -alkyl) 2) - (C 1 -C 4) -alkylene- (C 3 -C 6 ) -cycloalkyl,
  • R4 is -N (R6) 2, wherein R6 are the same or different and independently of one another
  • cycloalkyl is selected from the group consisting of cyclohexyl, cyclopentyl, cyclopropyl, adamantanyl, 1, 7, 7 - Trimethyl-bicyclo [3.1.1] heptanyl, tetrahydro-naphthalenyl, decahydro-naphthalenyl, octahydro-4,7-methano-indenyl or bicyclo [2.2.1] heptanyl and wherein cycloalkyl unsubstituted or independently of one another once, twice or three times by - (C 1 -C 4) -alkyl or pheny! is substituted,
  • Benzimidazolyl isoxazolyl, piperidinyl, pyridinyl, pyrrolidinyl, thiophenyl and benzo [1,3] dioxolyl,
  • Bicyclo [3.1.1] heptanyl is unsubstituted or substituted one to four times by - (C 1 -C 4) -alkyl; 14) - (C 1 -C 6) -alkylene-C (O) -O-R 11, where alkylene is unsubstituted or independently of one another by chlorine, fluorine, -C (O) -O-RH, - (C-C4) -alkyl-O-R11, -O- (Ci-C4) alkyl, phenyl or - (C 1 -C 4) -alkyl is substituted,
  • R 7 is hydrogen or - (C 1 -C 4) -alkyl
  • R 9 is hydrogen or - (C 1 -C 4) -alkyl
  • R11 and R12 are the same or different and independently of each other
  • cycloalkyl is selected from the group consisting cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantane tanyl, 1, 7,7- Trimethyl-bicyclo [3.1.1] heptanyl, octahydro-4,7-methano-indenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently of one another once, twice, three or four times by - (C-
  • R 14 is hydrogen, - (C 1 -C 4 ) -alkyl, -NH 2 or -OH and
  • R 15 is hydrogen, - (C 1 -C 4 ) -alkyl, -O-CF 3 , -NH 2 , -OH, -CF 3 or halogen.
  • the invention also relates to the use of the compound of formula I wherein X is -SO 2 -,
  • R1 for 1) hydrogen atom or
  • R 2 for 1) - (C 1 -C 6 ) -alkylene-NH 2 , 2) - (C 0 -C 4 ) -alkylene-pyridyl-NH 2 ,
  • R 3 is 1) - (C 1 -C 4 ) -alkyl
  • Het is a 4- to 15-membered heterocyclic ring system is understood with 4 to 15 ring atoms, which are present in one, two or three interconnected ring systems and the one, two, contain three or four identical or different heteroatoms from the series oxygen, nitrogen or sulfur, wherein Het or alkylene unsubstituted or independently of one another once, twice or three times by R 11, halogen, -C (O) -O-RH, - (C 1 -C 4 ) -alkyl-O-R 11 or -O- (Ci-C 4 ) Alkyl are substituted,
  • -C (O) -O-R11, - (Crj-C 4) are substituted alkyl-O-R11 or -O- (Ci-C4) alkyl,
  • Halogen - (C ⁇
  • R7 is hydrogen or - (C 1 -C 4 ) -alkyl
  • R 9 is hydrogen or - (C-
  • R11 and R12 are the same or different and independently of each other
  • Halogen -C (O) -O-RI 3, - (C 1 -C 4 ) alkyl-O-RIS, -O- (C 1 -C 4 ) -alkyl or - (C 1 -C 4 ) -alkylene-phenyl,
  • R 13 is 1) hydrogen
  • R14 represents hydrogen, - (C-
  • R 15 is hydrogen atom, - (C 1 -C 4 ) -alkyl, -O-CF 3 , -NH 2 , -OH, -CF 3 or halogen.
  • the invention also relates to the use of the compound of formula I wherein X is -SO 2 -,
  • R 1 represents 1) hydrogen or 2) - (C 1 -C 4 ) -alkyl
  • R 2 for 1) - (C 1 -C 6) -alkylene-NH 2 ,
  • R 3 represents 1) - (CiC 4) -alkyl
  • R 4 is hydrogen
  • R 4 is -N (R 6) 2 wherein R 6 are the same or different and independently of one another represents 1) hydrogen atom, 2) - (C 1 -C 4 ) 1-IkYl,
  • cycloalkyl is selected from the group tanyl cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantane, bicyclo [3.1.1] heptanyl, Decahydro-naphthalenyl, tetrahydronaphthalenyl, octahydro-4,7-methanoindenyl or bicyclo [2.2.1] heptanyl and wherein cycloalkyl is unsubstituted or independently substituted once, twice, three or four times by - (C-
  • cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, Cyclopropyl, adamantanyl, bicyclo [3.1.1] heptanyl, decahydro-naphthalenyl, tetrahydronaphthalenyl, octahydro-4,7-methanoindenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently of one, two, three or three or quadruply substituted by - (C 1 -C 4) -alkyl, -C (O) -O-R 11 or - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or
  • Benzisothiazolyl carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dibenzofuranyl, dibenzothiophenyl, dihydrofuran [2,3-b] tetrahydrofuranyl, dihydrofuranyl, dioxolyl , Dioxanyl, 2H, 6H-1, 5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
  • R11 and R12 are the same or different and independently of each other
  • R13 for 1) hydrogen atom
  • R 14 is hydrogen, - (C 1 -C 4 ) -alkyl, -NH 2 or -OH and R 15 is hydrogen, - (C 1 -C 4 ) -alkyl, -O-CF 3 , -NH 2 , -OH, -CF 3 or halogen.
  • the invention also relates to the use of the compound of the formula I, wherein X is -SO 2 -, R 1 is 1) hydrogen or
  • R 2 for 1) - (C 1 -C 6) -alkylene-NH 2, 2) - (C 1 -C 4) -alkylene-pyridyl-NH 2,
  • R 3 is 1) - (C 1 -C 4) -alkyl
  • R4 is -N (R6) 2, where R6 are identical or different and independently of one another represent 1) hydrogen atom,
  • cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclopropyl, adamantanyl, 1, 7,7-trimethyl-bicyclo [3.1.1] heptanyl, Decahydro-naphthalenyl, octahydro-4,7-methano-indenyl or bicyclo [2.2.1] heptanyl and wherein cycloalkyl is unsubstituted or independently mono-, di- or trisubstituted by - (C 1 -C 4) -alkyl or phenyl .
  • Benzimidazolyl isoxazolyl, piperidinyl, pyridyl, pyrrolidinyl, thiophenyl and benzo [1,3] dioxolyl, 7) 1,2,3,4-tetrahydro-naphthalenyl, 8) - (Co-C4) -alkylene-C (R11) (R12) -phenyl, where phenyl is unsubstituted or independently of one another mono-, di- or trisubstituted by phenyl or fluorine,
  • Bicyclo [3.1.1] heptanyl is unsubstituted or substituted one to four times by - (C 1 -C 4) -alkyl,
  • R11 and R12 are the same or different and independently of each other
  • cycloalkyl is selected from the group consisting cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl !, adamantanyl,
  • R 13 is 1) hydrogen
  • R 14 is hydrogen, - (C 1 -C 4 ) -alkyl, -NH 2 or -OH and R 15 is hydrogen, - (C 1 -C 4 ) -alkyl, -O-CF 3 , -NH 2, -OH , -CF3 or halogen.
  • the invention also relates to the use of the compound of the formula I, which is characterized in that it is one or more diseases from the series myocardial infarction, angina pectoris and other forms of acute coronary syndrome, stroke, peripheral vascular diseases, deep vein thrombosis, pulmonary embolism, embolic or thrombotic events due to cardiac arrhythmias, cardiovascular events such as restenosis after revascularization and angioplasty and similar procedures such as stenting and bypass surgery, or the reduction of the risk of thrombosis following surgery such as knee and hip replacement surgery, or the disseminated intravascular coagulation, sepsis and other intravascular events associated with inflammation, atherosclerosis, diabetes and the metabolic
  • tumor growth and tumor metastasis inflammatory and degenerative joint diseases such as rheumatoid arthritis and arthrosis, disorders of the hemostatic system such as fibrin deposits, fibrotic changes in the lung such as chronic obstructive pulmonary disease, adult respiratory distress syndrome or fibrin deposition of the eye following ocular surgery or prevention or treatment of scarring.
  • inflammatory and degenerative joint diseases such as rheumatoid arthritis and arthrosis
  • disorders of the hemostatic system such as fibrin deposits, fibrotic changes in the lung such as chronic obstructive pulmonary disease, adult respiratory distress syndrome or fibrin deposition of the eye following ocular surgery or prevention or treatment of scarring.
  • the invention further relates to the compound of the formula I.
  • X is -SO 2 -
  • R1 for 1) hydrogen atom
  • n is the integer zero, 1, 2 or 3,
  • A2 is 1) Het, Het being a 4 - to 15-membered heterocyclic
  • Ring system comprising 4 to 15 ring atoms which are present in one, two or three interconnected ring systems and which contain one, two, three or four identical or different heteroatoms from the series oxygen, nitrogen or sulfur and are unsubstituted or independently of one another, two or three times by a - (C 1 -C 3) -alkyl, halogen,
  • R4 is -N (R6) 2, wherein R6 are the same or different and independently of one another
  • -C 4) - Alkyl are substituted,
  • Het is a 4- to 15-membered heterocyclic ring system is understood with 4 to 15 ring atoms, which are present in one, two or three interconnected ring systems and the one, two, contain three or four identical or different heteroatoms from the series oxygen, nitrogen or sulfur, wherein Het or alkylene unsubstituted or independently of one, two or three times by R 11, halogen, -C (O) -O-RH, - (C 1 -C 4 ) -alkyl-O-R 11 or -O- (C 1 -C 4 ) -alkyl,
  • Halogen - (C 1 -C 4 ) -alkyl-O-R 11 or phenyl
  • R 5 is hydrogen or (C 1 -C 6 ) -alkyl
  • PG is a protective group for the amino, carboxyl or for the hydroxyl function
  • R7 is hydrogen or - (C-i-C ⁇ J-alkyl
  • R 8 is hydrogen or - (C 1 -C 6) -alkyl
  • R 9 is hydrogen or - (C 1 -C 6) -alkyl
  • R11 and R12 are the same or different and independently of each other
  • Alkyl is substituted
  • R14 is hydrogen, - (C-
  • the invention further relates to the compound of formula I, wherein X is -SO 2 -,
  • R 1 represents 1) hydrogen or 2) - (C 1 -C 4 ) -alkyl
  • R 3 is 1) - (C 1 -C 4) -alkyl
  • Het a 4- to 15-membered heterocyclic ring system is understood with 4 to 15 ring atoms, which in are one, two or three interconnected ring systems and contain one, two, three or four identical or different heteroatoms from the series oxygen, nitrogen or sulfur, wherein Het or alkylene is unsubstituted or independently one, two or three times by R11, Halogen, -C (O) -O-RH, - (C 1 -C 4 ) -alkyl-O-R 11 or -O- (C 1 -C 4 ) -alkyl,
  • R 13 is 1) hydrogen
  • R 14 is hydrogen, - (C 1 -C 4) -alkyl, -NH 2 or -OH, and R 15 is hydrogen, - (C 1 -C 4 ) -alkyl, -O-CF 3, -NH 2, -OH, - CF3 or
  • Halogen is available.
  • the invention also relates to the use of the compound of the formula I in which X is -SO 2 -, R 1 is 1) hydrogen or 2) - (C 1 -C 4 -alkyl), R 2 is 1) - (C 1 - C6) alkylene-NH2,
  • R4 is hydrogen
  • R4 is -N (R6) 2, where R6 are the same or different and independently of one another
  • Het is selected from the group acridinyl, azepinyl, azetidinyl, aziridinyl, benzimidazalinyl, benzimidazolyl,
  • R 11 and R 12 are identical or different and independently of one another represent 1) hydrogen atom, 2) - (C 1 -C 4) alkyl,
  • heptanyl decahydro-naphthalenyl, tetrahydronaphthalenyl, octahydro-4,7-methano-indenyl or bicyclo [2.2.1] -heptanyl and in which cycloalkyl is unsubstituted or independently of one another once, twice, three or four times by - (C-) C 1 -C 4) -alkyl, -C (O) -O-RI 3 or phenyl, or
  • R 13 is 1) hydrogen
  • R 14 is hydrogen, - (C 1 -C 4 ) -alkyl, -NH 2 or -OH and R 15 is hydrogen, - (C 1 -C 4 ) -alkyl, -O-CF 3 , -NH 2, -OH , -CF3 or halogen.
  • the invention also relates to the use of the compound of the formula I in which X is -SO 2 -, R 1 is 1) hydrogen or 2) - (C 1 -C 4) -alkyl,
  • R 3 is 1) - (C 1 -C 4 -alkyl, 2) - (C 1 -C 4 ) alkylene- (C3-C6) -cycloalkyl,
  • R4 is hydrogen
  • R4 is -N (R6) 2 , where R6 are the same or different and independently of one another
  • cycloalkyl is selected from the group consisting of cyclohexyl, cyclopentyl, cyclopropyl, adamantanyl, 1, 7,7-
  • Benzimidazolyl isoxazolyl, piperidine, pyridine, pyrrolidinyl, thiophenyl and benzo [1,3] dioxole, 7) 1,2,3,4-tetrahydro-naphthalenyl, 8) - (Co-C4) -alkylene-C (R11) (R12) -phenyl, where phenyl is unsubstituted or independently of one another mono-, di- or trisubstituted by phenyl or fluorine,
  • Bicyclo [3.1.1] heptanyl is unsubstituted or substituted one to four times by - (C 1 -C 4) -alkyl,
  • R11 and R12 are the same or different and independently of each other
  • R13 for 1) hydrogen atom
  • R14 is hydrogen atom, is - (Ci-C 4) alkyl, -NH 2 or -OH, and R15 is hydrogen atom, - (C-
  • the invention also relates to the compound of formula I and / or a stereoisomeric form of the compound of formula I and / or mixtures of these forms in any ratio, and / or a physiologically acceptable salt of
  • X is -C (O) -, R1 is 1) hydrogen atom,
  • n is the integer zero, 1, 2 or 3,
  • Ring system comprising 4 to 15 ring atoms which are present in one, two or three interconnected ring systems and which contain one, two, three or four identical or different heteroatoms from the series oxygen,
  • R4 is -N (R6) 2, where R6 are the same or different and independently of one another
  • Het is a 4- to 15-membered heterocyclic ring system is understood with 4 to 15 ring atoms, which are present in one, two or three interconnected ring systems and the one, two, contain three or four identical or different heteroatoms from the series oxygen, nitrogen or sulfur, wherein Het or alkylene is unsubstituted or independently of one another once, twice or three times by R11, halogen, -C (O) -O-RH, - (C ⁇ C 1 -C 4) -alkyl-O-R 11 or -O- (C 1 -C 4) -alkyl,
  • Binding takes place and the carboxyl radical of the amino acid is unsubstituted or substituted by PG or by -N (R5) 2, or the two radicals R6 together with the N-atom to which they are attached, a mono- or bicyclic ring with 4 to 9 ring atoms which is saturated, partially saturated or aromatic, the ring being unsubstituted or mono- or disubstituted by - (C 1 -C 4) -alkyl, -C (O) -O-R 11,
  • Halogen (C 1 -C 4) -alkyl-O-R 11 or phenyl, R 5 is hydrogen or (C 1 -C 6) -alkyl,
  • PG is a protective group for the amino, carboxyl or for the hydroxyl function
  • R 7 is hydrogen or - (C 1 -C 6) -alkyl
  • R 8 is hydrogen or - (C 1 -C 6) -alkyl
  • R 9 is hydrogen or - (C 1 -C 6) -alkyl
  • R 11 and R 12 are identical or different and independently of one another represent 1) hydrogen atom, 2) - (C 1 -Ce) -Alkyl,
  • R 13 is 1) hydrogen
  • R 14 is hydrogen, - (C 1 -C 4 ) -alkyl, -NH 2 or -OH
  • R 15 is hydrogen, - (C 1 -C 4 ) -alkyl, -O-CF 3 , -NH 2 , -OH, -CF 3 or halogen.
  • the invention also relates to the compound of formula I wherein X is -C (O) -, R1 is 1) hydrogen or
  • R 2 for 1) - (C 1 -C 6) -alkylene-NH 2 , 2) - (Co-C 4 ) -alkylene-pyridyl-NH 2 ,
  • R3 is 1) - (C ⁇ C- 4 ) -alkyl
  • R4 is -N (R6) 2, where R6 are identical or different and independently of one another represent 1) hydrogen atom,
  • Het is a 4- to 15-membered heterocyclic ring system is understood with 4 to 15 ring atoms, which are present in one, two or three interconnected ring systems and the one, two, three or four identical or different heteroatoms from the series
  • R 7 is hydrogen or - (C 1 -C 4) -alkyl
  • R 9 is hydrogen or - (C 1 -C 4) -alkyl
  • R11 and R12 are the same or different and independently of each other
  • Halogen -C (O) -O-RI 3, - (C 1 -C 4) -alkyl-O-R 13, -O- (C 1 -C 4) -alkyl or
  • R 13 is 1) hydrogen
  • R14 is hydrogen atom, - (C ⁇
  • R 15 is hydrogen, - (C 1 -C 4 ) alkyl, -O-CF 3 , -NH 2 , -OH, -CF 3 or halogen.
  • the invention also relates to the compound of formula I wherein X is -C (O) -, R 1 represents 1) hydrogen or 2) - (C 1 -C 4) -alkyl,
  • R 3 is 1) - (C 1 -C 4 -alkyl-, 2) - (C 1 -C4) -alkylene- (C 3 -C 6 ) -cycloalkyl,
  • R4 is -N (R6) 2 , wherein R6 are the same or different and independently of one another
  • cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, 1, 7,7-trimethyl-bicyclo [3.1.
  • heptanyl decahydro-naphthalenyl, tetrahydronaphthalenyl, octahydro-4,7-methanoindenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently of one another mono-, di-, tri- or tetra-substituted by - ( Ci-C4) alkyl,
  • Benzisothiazolyl carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dibenzofuranyl, dibenzothiophenyl, dihydrofuran [2,3-b] tetrahydrofuranyl, dihydrofuranyl, dioxolyl , Dioxanyl, 2H, 6H-1, 5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
  • Triazolyl 1, 2,3-triazolyl, 1, 2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl, wherein Het or alkylene is unsubstituted or independently of one another or by - (CjC ⁇ alkyl substituted
  • R 7 is hydrogen or - (C 1 -C 4) -alkyl
  • R 9 is hydrogen or - (C 1 -C 4) -alkyl
  • R11 and R12 are the same or different and independently of each other
  • cycloalkyl is selected from the group consisting of cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl,
  • R 13 is 1) hydrogen
  • R 14 is hydrogen, - (C 1 -C 4) -alkyl, -NH 2 or -OH and R 15 is hydrogen, - (C 1 -C 4 -alkyl, -O-CF 3 , -NH 2 , -OH, -CF3 or halogen.
  • the invention also relates to the compound of formula I wherein X is -C (O) -,
  • R1 for 1) hydrogen atom or
  • R 2 for 1) - (C 1 -C 6 ) -alkylene-NH 2 , 2) - (C 1 -C 4) -alkylene-pyridyl-NH 2)
  • R 3 is 1) - (C 1 -C 4) -alkyl
  • R 4 is hydrogen
  • R 4 is -N (R 6) 2 , where R 6 are identical or different and independently of one another represent 1) hydrogen, 2) - (C 1 -C 6 -alkyl,
  • cycloalkyl is selected from the group consisting cyclohexyl, cyclopentyl, cyclopropyl, adamantanyl, 1, 7,7-trimethyl-bicyclo [3.1.1] heptanyl , Decahydro-naphthalenyl, octahydro-4,7-methano-indenyl or bicyclo [2.2.1] heptanyl and wherein cycloalkyl is unsubstituted or independently of one another monosubstituted, disubstituted or trisubstituted by - (C 1 -C 4) -alkyl or phenyl,
  • Benzimidazolyl isoxazolyl, piperidinyl, pyridyl, pyrrolidinyl, thiophenyl and benzo [1,3] dioxolyl,
  • R 7 is hydrogen or - (C 1 -C 4) -alkyl
  • R 9 is hydrogen or - (C 1 -C 4) -alkyl
  • R 11 and R 12 are the same or different and are each independently
  • cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, 1, 7,7-trimethyl-bicyclo [3.1.1] heptanyl, decahydro-naphthalenyl, octahydro-4,7-methano-indenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently of one another, one, two, three or four times by C 1 -C 4) -alkyl, -C (O) -O-RI 3 or phenyl, or
  • R14 is hydrogen atom, - (C 1 -C 4 J-AIlCyI 1 -NH 2 or -OH and R15 represents hydrogen atom, - (C-
  • (C-i-C ⁇ J-alkyl) hydrocarbon radicals whose
  • Carbon chain is straight-chain or branched and contains 1 to 6 carbon atoms, for example methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, iso-pentyl, neo-pentyl, hexyl, 2,3-dimethylbutane or neohexyl ,
  • - (Co-C4) -alkylene means hydrocarbon radicals whose carbon chain is straight-chain or branched and contains 1 to 4 carbon atoms, for example methylene, ethylene, propylene, iso-propylene, iso-butylene, butylene or tertiary-butylene, "- Cr j -alkylene" is a covalent bond.
  • - (CH 2) rr. where n is the integer zero or 1 "is the radical methylene for the case n is equal to 1 and in the case where n is the integer zero, the radical has the meaning of a covalent bond --C-C4)
  • -alkylene are hydrocarbon radicals whose carbon chain is straight-chain or branched and contains 1 to 4 carbon atoms, for example methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -), propylene (-CH 2 -CH 2 -CH 2 -), iso-propylene, iso-butylene, butylene or tertiary-butylene.
  • n is the integer zero, 1, 2 or 3
  • radicals such as methylene, ethylene or propylene are understood, and in the case where n is zero, the radical has the meaning of a covalent bond -C-12) -Cycloalkyl
  • radicals are understood as compounds derived from 3- to 12-membered mono-, bi- or tricyclene or bridging cycles such as the monocycles cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane or cyclooctane, the derived from the bicyclic bicyclo [4.2.0] octane, octahydroindene, decahydro-naphthalene, decahydro-azulene, decahydrobenzocycloheptene or dodecahydroheptalen, or from tricyclic compounds such as adamantane or
  • R6 together with the N-atom to which they are attached form a mono- or bicyclic ring having 4 to 9 ring atoms is understood to mean radicals such as compounds derived from 4- to 8-membered monocycles which are saturated or entirely or partially aromatic, for example, azetidine, dihydroacetate, acetone, diazetidine, diacetate, pyrrolidine, dihydropyrrole, pyrrole, imidazolidine, dihydroimidazole, imidazole, pyrazoline, pyrazolidine, piperidine, dihydropyridine, tetrahydropyridine, pyridine, piperazine, dihydropyrazine, pyrazine, pyridazine, pyrimidine , Oxazine, azepane, tetrahydroazepine, azepine, azocane, dihydroazocine, hexohydroazocine or azocine or bicyclic rings
  • - (Cg-C 14) -Ary I is understood to mean aromatic carbon radicals having from ⁇ to 14 carbon atoms in the ring - (C 9 -C 14) -Aryl radicals are, for example, phenyl, naphthyl, for example 1-naphthyl, 2 Naphthyl, 1,2,3,4-tetrahydronaphthalenyl, anthryl or fluorenyl. Naphthyl radicals and in particular phenyl radicals are preferred aryl radicals.
  • Het 4- to 15-membered Het ring
  • Het is understood as meaning ring systems having 4 to 15 carbon atoms which are present in one, two or three interconnected ring systems and which are one, two, three or four identical or different Heteroatoms from the series oxygen, nitrogen or sulfur included.
  • ring systems are the radicals acridinyl, azepinyl, azetidinyl, aziridinyl, benzimidazalinyl, benzimidazolyl, benzo [1,3] dioxole, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl , Carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, deca-hydroquinolinyl, dibenzofuranyl, dibenzothiophenyl, dihydrofuran [2,3-b
  • Preferred Het rings are the radicals isoxazolyl, benzo [1, 3] dioxole and thiophenyl.
  • halogen is understood to mean fluorine, chlorine, bromine or iodine, preference is given to fluorine, chlorine or bromine, in particular chlorine or bromine.
  • amino acid includes compounds such as naturally occurring ⁇ -amino acids glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid and Particular preference is given to histidine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, arginine, glutamic acid and aspartic acid, as well as non-naturally occurring amino acids such as 2-aminoadipic acid, 2-aminobutyric acid, 2-aminoisobutyric acid , 2,3-diamino-propionic acid, 2,4-diaminobutyric acid, 1, 2,3,4-tetra-hydroisoquinoline-1-carboxy
  • protecting group for the amino, carboxyl or for the hydroxyl function is understood to mean protective groups such as suitable protective groups for amino functions, for example the t-butoxycarbonyl, the benzyloxycarbonyl or the phthalolyl group and the trityl or tosyl protecting group
  • suitable protective groups for the Carboxyl function are, for example, alkyl, aryl or arylalkyl esters
  • suitable protecting groups for the hydroxy function are, for example, alkyl esters, t-butyl, benzyl or trityl groups
  • Protecting groups can be introduced and removed by well-known or described techniques (see Green, TW, Wutz, PGM, Protective Groups in Organic Synthesis (1991), 2nd Ed., W ⁇ ley-Interscience, or Kocienski, P., Protecting Groups (1994), Thieme).
  • Alkyl radical derived, for example, from the following radicals -CF3, -CHF 2 , -CH 2 F, -CHF-CF 3 , -CHF-CHF 2 , -CHF-CH 2 F, -CH 2 -CF 3 , -CH 2 -CHF 2 , -CH 2 -CH 2 F, -CF 2 -CF 3 , -CF 2 -CHF 2 , -CF 2 -CH 2 F, -CH 2 -CHF-CF 3 , -CH 2 -CHF- CHF 2 , -CH 2 -CHF-CH 2 F, -CH 2 -CH 2 -CF 3 , -CH 2 -CH 2 -CHF 2 , -CH 2 -CH 2 -CH 2 F, -CH 2 -CF 2 -CF 3 , -CH 2 -CH 2 -CHF 2 , -CH 2 -CH 2 F, -CH 2 -CF 2 -
  • the invention further relates to a process for the preparation of the compound of the formula I 1, which comprises reacting a) a compound of the formula II
  • R 2 where R 2 and PG have the meanings given in the compound of the formula I, with a phosgene equivalent such as carbonyldiimidazole, diphosgene, triphosgene or phosgene to give an intermediate compound of the formula III,
  • R2 and PG have the meanings given in the compound of the formula I, and the compound of the formula III with an amino acid of the formula IV,
  • R 2, R 3, R 4 and PG have the meanings given in the compound of the formula I, and then converted into a compound of the formula I, or b) a compound of the formula II is reacted with a compound of the formula IX,
  • the compound of the formula I prepared according to the methods a) b) or c) is either isolated in free form or, in the case of the presence of acidic or basic groups, converted into physiologically acceptable salts.
  • the compounds of the formula (I) according to the invention are prepared, for example, by treating amino acid (II) with a phosgene equivalent such as carbonyldiimidazole, diphosgene, triphosgene or phosgene in an inert solvent such as DMF or dichloromethane and the resulting intermediate (III) with a commercially available or by deprotecting amino acid (IV) to give a compound (V), wherein PG is as defined in the compound of formula I.
  • a phosgene equivalent such as carbonyldiimidazole, diphosgene, triphosgene or phosgene in an inert solvent such as DMF or dichloromethane
  • a further process for preparing the compounds of the invention according to (I) is the reaction of the compounds (IX) with compounds of the type (II) analogously to A.
  • compounds of the formula X are prepared, which are subsequently deprotected and give compounds of the formula I:
  • Amines of the formula NH (R 6) 2 are understood as meaning commercially available amines or dipeptide derivatives prepared by methods known from the literature.
  • the compounds (II) are commercially available or can be prepared by alkylation of tert-butyl (benzhydrylidene-amino) -acetate in suitable solvents such as THF or DMF under the action of bases such as lithium hexa-methyldisilazane, KOH, NaOH, CsOH, K2CO3 or NaH and subsequent deprotection under acidic
  • a compound of the formula I prepared according to Scheme 1 or 3, or a suitable precursor of the formula I, which occurs in enantiomeric forms because of its chemical structure, can be formed by salt formation with enantiomerically pure acids or bases, chromatography on stationary chiral phases or derivatization using chiral enantiomerically pure compounds such as amino acids , Separation of the thus obtained diastereomers, and cleavage of the chiral auxiliary groups are separated into the pure enantiomers (process b), or the compound of formula I prepared according to Scheme 1 or 3 can either isolated in free form or in the presence of acidic or basic Groups are converted into physiologically acceptable salts (method d).
  • the compound of formula I if it occurs as a mixture of diastereomers or enantiomers or obtained in the selected synthesis as mixtures thereof, separated into the pure stereoisomers, either by chromatography on an optionally chiral support material, or, if the racemic Compound of formula I is capable of salt formation, by fractional crystallization of diastereomeric salts formed with an optically active base or acid as an excipient.
  • Suitable chiral stationary phases for the thin-layer or column chromatographic separation of enantiomers are, for example, modified silica gel carriers (so-called Pirkle phases) and high molecular weight carbohydrates such as triacetylcellulose.
  • gas chromatographic methods can also be used on chiral stationary phases according to appropriate derivatization known to the person skilled in the art.
  • an optically active, usually commercially available base such as (-) - nicotine, (+) - and (-) - phenylethylamine, quinine bases, L-lysine or L- and D-arginine the different soluble formed diastereomeric salts, the less soluble component as a solid isolated, the more readily soluble diastereomer from the mother liquor deposited and recovered from the thus obtained diastereomeric salts, the pure enantiomers.
  • racemic compounds of formula I which contain a basic group such as an amino group
  • optically active acids such as (+) - camphor-10-sulfonic acid, D- and L-tartaric acid, D- and L- Convert lactic acid and (+) and (-) - mandelic acid into the pure enantiomers.
  • Carboxylic acids with carboxy protected enantiomerically pure amino acids in the amides or with enantiomerically pure hydroxycarboxylic acids such as lactic acid, in the corresponding chiral esters can be used to separate the isomers, by separating the now present diastereomers by crystallization or chromatography performs appropriate stationary phases and then splits off the entrained chiral part of the molecule by means of suitable methods.
  • diastereo- or enantiomerically pure starting materials for the preparation of the framework structures.
  • other or simplified methods for the purification of the end products can be used.
  • These starting materials were previously prepared by literature methods enantiomeren- or diastereomerenrein. This may in particular mean that either enantioselective processes are used in the synthesis of the basic frameworks, or else an enantiomeric (or diastereomeric) separation is carried out at an early stage of the synthesis and not at the stage of the final products. Likewise, a simplification of the separations can be achieved by acting in two or more stages.
  • Acidic or basic products of the compound of formula I may be in the form of their salts or in free form.
  • pharmacologically acceptable salts for example alkali metal or alkaline earth metal salts such as hydrochlorides, hydrobromides, sulfates, hemisulfates, all possible phosphates and salts of the amino acids, natural bases or carboxylic acids.
  • the preparation of physiologically compatible salts of salts of compounds of the formula I capable of salt formation, including their stereoisomeric forms, according to process step c) is carried out in a manner known per se.
  • the compounds of formula I form with basic reagents such as hydroxides, carbonates, bicarbonates, alcoholates and ammonia or organic bases, for example trimethyl or triethylamine, ethanolamine, diethanolamine or triethanolamine, trometamol or basic amino acids, such as lysine, ornithine or arginine, stable alkali , Alkaline earth or optionally substituted ammonium salts.
  • basic reagents such as hydroxides, carbonates, bicarbonates, alcoholates and ammonia or organic bases, for example trimethyl or triethylamine, ethanolamine, diethanolamine or triethanolamine, trometamol or basic amino acids, such as lysine, ornithine or arginine, stable alkali , Alkaline earth or optionally substituted am
  • both inorganic and organic acids such as hydrochloric, hydrobromic, sulfuric, hemic-sulfuric, phosphoric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, 4- Bromobenzenesulfone, cyclohexylamidosulfone, trifluoromethylsulfone, 2-hydroxyethanesulfonic, acetic, oxalic, tartaric, succinic, glycerophosphoric, lactic, malic, adipic, citric, fumaric, maleic, glucone -, Glucuron- palmitic acid, or trifluoroacetic acid in question.
  • inorganic and organic acids such as hydrochloric, hydrobromic, sulfuric, hemic-sulfuric, phosphoric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, 4- Bromobenz
  • the invention also relates to pharmaceutical compositions, characterized by an effective content of at least one compound of formula I and / or a physiologically acceptable salt of the compound of formula I and / or an optionally stereoisomeric form of the compound of formula I 1 together with a pharmaceutically acceptable and physiologically compatible carrier, additive and / or other active ingredients and excipients.
  • the compounds according to the invention are suitable for the prophylaxis, secondary prevention and therapy of all diseases which can be treated by an inhibition of TAFIa.
  • TAFIa inhibitors are suitable both for a prophylactic and for a therapeutic application in humans. They are suitable for both acute treatment and long-term therapy.
  • TAFIa inhibitors may be used in patients suffering from disorders of well-being or diseases associated with thrombosis, embolism, hypercoagulability or fibrotic changes.
  • TAFIa inhibitors can be used in all procedures that lead to a contact of the blood with foreign surfaces such. As in dialysis patients and patients with indwelling catheters. TAFIa inhibitors can be used to reduce the risk of thrombosis following surgical procedures such as knee and hip joint surgery.
  • TAFIa inhibitors are useful in the treatment of patients with disseminated intravascular coagulation, sepsis, and other intravascular events associated with inflammation. Furthermore, TAFIa inhibitors are suitable for the prophylaxis and treatment of patients with atherosclerosis, diabetes and the metabolic syndrome and their consequences. Disorders of the hemostatic system (eg fibrin deposits) have been implicated in mechanisms leading to tumor growth and tumor metastasis, as well as in inflammatory and degenerative joint diseases such as rheumatoid arthritis and osteoarthritis. TAFIa inhibitors are useful for slowing down or preventing such processes.
  • TAFIa inhibitors are fibrotic changes of the lung such as the chronic obstructive pulmonary disease, the adult respiratory distress syndrome (ARDS) and the eye such as fibrin deposits after eye surgery.
  • TAFIa inhibitors are also useful in the prevention and / or treatment of scarring.
  • the application of the medicaments according to the invention can be effected by oral, inhalative, rectal or transdermal administration or by subcutaneous, intra-articular, intraperitoneal or intravenous injection.
  • the oral application is preferred. Coating with TAFIa inhibitors of stents and other surfaces that come in contact with blood in the body is possible.
  • the invention also relates to a process for the preparation of a medicament, which comprises bringing at least one compound of the formula I into a suitable administration form with a pharmaceutically suitable and physiologically acceptable carrier and optionally further suitable active substances, additives or excipients.
  • Suitable solid or galenic forms of preparation are, for example, granules, powders, dragees, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions, as well as preparations with protracted release of active ingredient, in the preparation of which conventional auxiliaries such as excipients, disintegrants, binders, coating substances, swelling agents, lubricants or lubricants, flavorings, sweeteners and solubilizers are used.
  • conventional auxiliaries such as excipients, disintegrants, binders, coating substances, swelling agents, lubricants or lubricants, flavorings, sweeteners and solubilizers are used.
  • Commonly used adjuvants are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and theirs
  • animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycol and solvents such as sterile water and monohydric or polyhydric alcohols such as glycerol, called.
  • the pharmaceutical preparations are prepared and administered in dosage units, each unit containing as active ingredient a specific dose of the compound of formula I according to the invention.
  • this dose may be up to about 1000 mg, but preferably about 50 to 300 mg and for injection solutions in ampoule form up to about 300 mg, but preferably about 10 to 100 mg.
  • daily doses for the treatment of an adult patient weighing about 70 kg, depending on the efficacy of the compound according to formula I, daily doses of about 2 mg to 1000 mg of active ingredient, preferably about 50 mg to 500 mg, are indicated. However, higher or lower daily doses may be appropriate.
  • the administration of the daily dose can be carried out by single administration in the form of a single unit dose or several smaller dosage units as well as by multiple subdivided doses at specific intervals.
  • TAFIa inhibitors can be used both as monotherapy and in combination or together with all antithrombotics (anticoagulants and
  • Platelet aggregation inhibitors Platelet aggregation inhibitors
  • thrombolytic agents plasmaogen activators of any kind
  • other profibrinolytic agents include antihypertensives, regulators of blood sugar, lipid lowering agents and antiarrhythmic agents.
  • End products are usually determined by mass spectroscopic methods (FAB, ESI-MS) and 1 H-NMR, indicated in each case the main peak or the two main peaks.
  • Method B Acid: YMC Jsphere 33x2.1 mm, packing material 4 ⁇ m, eluent: CH3CN + 0.05% TFA: H2O + 0.05% TFA, gradient: 5:95 (0 min.) To 95: 5 (2 , 5 min.) To 95: 5 (3.0 min), flow: 1, 3 mL / min, temperature: 30 ° C.
  • Method C Column: YMC Jsphere 33x2.1 mm, packing material 4 ⁇ m, eluent: CH 3 CN + 0.08% formic acid: H 2 O + 0.1% formic acid, gradient: 5:95 (0 min.) To 95: 5 (2 ., 1, 3 mL / min temperature::, 5) minutes after the 95: 5 (3.0 min), river. 30 0 C.
  • Acetonitrile + 0.1% TFA 1 flow 25 ml / min, 0-7 min. 100% A, 7-22 min. at 100% B, 22-30 min. 100% B, 30-33 min. at 100% A, 33-35 min. 100% A.
  • the evaporation of solvents was usually carried out under reduced pressure at 35 0 C to 45 0 C on a rotary evaporator.
  • Example 143d To the solution obtained in Example 143d) was added a suspension of 5.39 g H-Lys (Boc) -OtBu hydrochloride (15.9 mmol, 1.0 eq) and 7.1 mL triethylamine (50.9 mmol, 3, 2 eq) in dichloromethane (7OmL) was added so that the temperature did not exceed 10 0 C. Upon completion of the addition, it was allowed to come to RT and stir for an additional 2 hours. The reaction mixture was then treated with 200 ml of 0.2 M hydrochloric acid, the organic phase was separated and washed with 100 ml of 0.2 M hydrochloric acid and concentrated.
  • the reaction mixture was stirred at 80 ° C. for 20 h and, after cooling, evaporated.
  • the crude product was purified by chromatography on silica gel with heptane / ethyl acetate mixtures as eluent. There were obtained 275 mg of the title compound.
  • Example 164 3- (6-Amino-pyridin-3-ylmethyl) -2 - [(S) -2-cyclohexyl-1 - ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo] .iJhept ⁇ -ylcarbamoyl-ethylsulfamidyl-propionic acid 1) tert-butyl 2-amino-3- (6-tert-butoxycarbonylaminopyridin-3-yl) propionate 660 mg of N- (diphenylmethylene) glycine tert-butyl ester (2.23 mmol, 1 equiv) were dissolved in 15 mL of dry THF and cooled to 0 ° C.
  • LiHMDS lithium hexamethyldisilazane
  • the substances produced were tested for inhibition of TAFIa with the Actichromic Plasma TAFI Activity Kit from American Diagnostica (Pr. No. 874).
  • 28 ⁇ l of test buffer (20 mM Hepes, 15 mM NaCl, pH 7.4) and 10 ⁇ L TAFIA (American Diagnostica No. 874TAFIA, 2.5 / ml) were added to 2 ⁇ l of 2.5 mM DMSO solution of the substance Incubated for 15 minutes at RT in a 96-well-well microtiter plate.
  • the enzyme reaction was monitored by addition of 10 ⁇ L TAFIa "Developer" (1: 2 with assay buffer prediluted) started. The time course of the reaction was at 420 nm in one
  • Microplate reader (SpectraMax plus 384, Molecular Devices) followed for 15 minutes.
  • the IC 5 o values were calculated from the averaged values (duplicate determination)

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Abstract

The invention relates to compounds of formula (I) which are inhibitors of activated thrombin-activatable fibrinolysis inhibitor. Said compounds of formula (I) are suitable for producing medicaments used for the prevention, secondary prevention, and treatment of one or several diseases associated with thromboses, embolisms, hypercoagulability, or fibrotic changes.

Description

Harnstoff- und Sulfamidderivate als Inhibitoren von TAFIa Urea and sulfamide derivatives as inhibitors of TAFIa
Die Erfindung betrifft neue Verbindungen der Formel I, die das Enzym TAFIa (aktivierter Thrombin-aktivierbarer Fibrinolyse Inhibitor) inhibieren, Verfahren zu ihrer Herstellung und Verwendung derselben als Arzneimittel.The invention relates to novel compounds of the formula I which inhibit the enzyme TAFIA (activated thrombin-activatable fibrinolysis inhibitor), processes for their preparation and use thereof as medicaments.
Das Enzym TAFIa entsteht beispielsweise durch Thrombinaktivierung aus dem Thrombin-aktivierbaren-Fibrinolyse-lnhibitor-Zymogen (TAFI). Das Enzym TAFI wird auch als Plasma Procarboxypeptidase B, Procarboxypeptidase U oder als Procarboxypeptidase R bezeichnet und ist ein Carboxypeptidase B ähnlichesThe enzyme TAFIa is formed, for example, by thrombin activation from the thrombin-activatable fibrinolysis inhibitor zymogen (TAFI). The enzyme TAFI is also referred to as plasma procarboxypeptidase B, procarboxypeptidase U or as procarboxypeptidase R and is a carboxypeptidase B like
Proenzym (L. Bajzar, Arterioscler. Thromb. Vase. Biol. 2000, Seiten 2511 - 2518).Proenzyme (L. Bajzar, Arterioscler, Thromb Vase, Biol., 2000, pp. 2511-2518).
Während einer Gerinnselbildung wird Thrombin als das Endprodukt der Koagulationskaskade generiert und induziert die Konversion von löslichem Plasmafibrinogen zu einer unlöslichen Fibrinmatrix. Gleichzeitig aktiviert Thrombin den endogenen Fibrinolyse-Inhibitor TAFI. Aktiviertes TAFI (TAFIa) entsteht also während der Thrombusbildung und der Lyse aus dem Zymogen TAFI unter der Einwirkung von Thrombin; Thrombomodulin im Komplex mit Thrombin verstärkt diesen Effekt etwa 1250 fach. TAFIa spaltet basische Aminosäuren am carboxy-Ende des Fibrins. Der Verlust der carboxy-terminalen Lysine als Bindestellen für Plasminogen führt dann zu einer Inhibition der Fibrinolyse. Effektive Inhibitoren von TAFIa verhindern den Verlust dieser hoch affinen Lysin-Bindungsstellen für Plasminogen und unterstützen auf diese Weise die endogene Fibrinolyse durch Plasmin: TAFIa Inhibitoren wirken profibrinolytisch.During clot formation, thrombin is generated as the end product of the coagulation cascade and induces the conversion of soluble plasma fibrinogen to an insoluble fibrin matrix. At the same time thrombin activates the endogenous fibrinolysis inhibitor TAFI. Activated TAFI (TAFIa) thus arises during thrombus formation and lysis from the zymogen TAFI under the action of thrombin; Thrombomodulin in complex with thrombin amplifies this effect about 1250 times. TAFIa cleaves basic amino acids at the carboxy end of fibrin. The loss of the carboxy-terminal lysines as binding sites for plasminogen then leads to an inhibition of fibrinolysis. Effective inhibitors of TAFIa prevent the loss of these high-affinity lysine binding sites for plasminogen and thus support endogenous fibrinolysis by plasmin: TAFIa inhibitors act profibrinolytically.
Um die Hämostase im Blut aufrechtzuerhalten, haben sich Mechanismen ausgebildet, die zur Blutgerinnung und zur Auflösung von Gerinnseln führen; diese stehen in einem Gleichgewicht. Wenn ein gestörtes Gleichgewicht die Koagulation begünstigt, entsteht Fibrin in größeren Mengen, so dass pathologische Vorgänge der Thrombusbildung zu schweren Krankheitsbildern im Menschen führen können.In order to maintain hemostasis in the blood, mechanisms have developed which lead to blood coagulation and the dissolution of clots; These are in balance. When a disturbed balance favors coagulation, fibrin is produced in larger quantities, so that pathological processes of thrombus formation can lead to serious clinical pictures in humans.
Genauso wie eine überschießende Koagulation zu schwerwiegenden thrombotisch bedingten Krankheitsbildern führen kann, besitzt eine antithrombotische Behandlung das Risiko von nicht erwünschten Blutungen durch eine Störung der Bildung eines notwendigen hämostatischen Pfropfs. Die Hemmung von TAFIa verstärkt - ohne die Koagulation und die Plättchenaggregation zu beeinflussen - die endogene Fibrinolyse d.h. das gestörte Gleichgewicht wird zugunsten der Fibrinolyse verschoben. So kann sowohl dem Aufbau eines klinisch relevanten Thrombus entgegengewirkt, als auch die Lyse eines schon bestehenden Gerinnsels verstärkt werden. Andererseits wird der Aufbau eines hämostatischen Pfropfs nicht beeinträchtigt, sodass eine Blutungsdiathese eher nicht zu erwarten ist (Bouma et al., J. Thrombosis and Haemostasis, 1, 2003, Seiten 1566 - 1574).Just as excessive coagulation can lead to serious thrombotic conditions, it has an antithrombotic treatment the risk of unwanted bleeding due to disruption of the formation of a necessary hemostatic plug. The inhibition of TAFIa - without affecting the coagulation and the platelet aggregation - enhances the endogenous fibrinolysis, ie the disturbed equilibrium, in favor of fibrinolysis. Thus, both the construction of a clinically relevant thrombus can be counteracted, as well as the lysis of an existing clot can be strengthened. On the other hand, the structure of a hemostatic graft is not compromised, so bleeding diathesis is unlikely to be expected (Bouma et al., J. Thrombosis and Haemostasis, 1, 2003, pages 1566-1574).
Inhibitoren von TAFIa sind bereits in der Internationalen Anmeldung WO2005/105781 beschrieben worden.Inhibitors of TAFIa have already been described in International Application WO2005 / 105781.
Die erfindungsgemäßen TAFIa Inhibitoren eignen sich für eine prophylaktische als auch für eine therapeutische Anwendung am Menschen, die an Erkrankungen leiden, die mit Thrombosen, Embolien, Hyperkoagulabilität oder fibrotischen Veränderungen einhergehen. Sie können zur Sekundär-Prevention eingesetzt werden und eignen sich sowohl für eine akute als auch für eine Langzeittherapie.The TAFIa inhibitors according to the invention are suitable for a prophylactic as well as for a therapeutic use in humans, which suffer from diseases that are associated with thromboses, embolisms, hypercoagulability or fibrotic changes. They can be used for secondary prevention and are suitable for both acute and long-term therapy.
Die Erfindung betrifft daher die Verwendung der Verbindung der Formel IThe invention therefore relates to the use of the compound of the formula I.
Figure imgf000003_0001
und/oder einer stereoisomeren Form der Verbindung der Formel I und/oder Gemische dieser Formen in jedem Verhältnis, und/oder ein physiologisch verträgliches Salz der Verbindung der Formel I, zur Herstellung eines Arzneimittels zur Prophylaxe, Sekundärprevention und Therapie einer oder mehrerer Erkrankungen, die mit Thrombosen, Embolien, Hyperkoagulabilität oder fibrotischen Veränderungen einhergehen, wobei X für -C(O)- oder -SO2- steht,
Figure imgf000003_0001
and / or a stereoisomeric form of the compound of formula I and / or mixtures of these forms in any ratio, and / or a physiologically acceptable salt of the compound of formula I, for the manufacture of a medicament for the prophylaxis, secondary prevention and therapy of one or more diseases associated with thrombosis, embolism, hypercoagulability or fibrotic changes, where X is -C (O) - or -SO 2 -,
R1 für 1) Wasserstoffatom, 2) -(C1-Ce)-AIKyI,R1 for 1) hydrogen atom, 2) - (C 1 -Ce) -Alkyl,
3) -(Co-C4)-Alkylen-(C3-Ci2)-Cycloalkyl oder3) - (Co-C4) -alkylene- (C3-Ci2) -cycloalkyl or
4) -(C -i -C6)-Alkylen-(C6-C 14)-Aryl steht,4) - (C 1 -C 6) -alkylene- (C 6 -C 14) -aryl,
R2 für den Rest der Formel Il -(A1)m-A2 (II) steht, worin m die ganze Zahl Null oder 1 bedeutet,R 2 is the radical of the formula II - (A1) m -A 2 (II), where m is the integer zero or 1,
A1 für 1) -(CH2)rr. worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet,A1 for 1) - (CH2) rr. where n is the integer zero, 1, 2 or 3,
2) -NH-(CH2)rr. worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet, 3) -NH(Ci -C6)-AlkylHCH2)n-, worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet,2) -NH- (CH 2) rr. where n is the integer zero, 1, 2 or 3, 3) -NH (C 1 -C 6 ) -alkylHCH 2) n -, where n is the integer zero, 1, 2 or 3,
4) -NH((C3-C6)-Cycloalky!)-(CH2)rr, worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet,4) -NH ((C 3 -C 6) -cycloalky!) - (CH 2) r r, where n is the integer zero, 1, 2 or 3,
5) -O-(CH2)n-> worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet, oder 6) -(CH2)n-SOx-, worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet und x die ganze Zahl Null, 1 oder 2 bedeutet, steht, A2 für 1) Het, wobei unter Het ein 4- bis 15-gliedriges heterocyclisches5) -O- (CH 2) n - > wherein n is the integer zero, 1, 2 or 3, or 6) - (CH 2) n -SO x -, where n is the integer zero, 1, 2 or 3 and x is the integer zero, 1 or 2, A2 is 1) Het, where Het is a 4- to 15-membered heterocyclic
Ringsystem mit 4 bis 15 Ringatomen verstanden wird, die in ein, zwei oder drei miteinander verbundenen Ringsystemen vorliegen und die ein, zwei, drei oder vier gleiche oder verschiedene Heteroatome aus derRing system is understood with 4 to 15 ring atoms, which are present in one, two or three interconnected ring systems and the one, two, three or four identical or different heteroatoms from the
Reihe Sauerstoff, Stickstoff oder Schwefel enthalten und unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch -(C1-C3)-Contain oxygen, nitrogen or sulfur and are unsubstituted or independently one, two or three times by - (C1-C3) -
Alkyl, Halogen, -NH2, -CF3 oder -O-CF3 substituiert sind, 2) -(C0-C6)-Alkylen-NH2, 3) -(C1-C6)-Alkylen-NH-C(=NH)-NH2,Alkyl, halogen, -NH 2, -CF 3 or -O-CF 3, 2) - (C 0 -C 6 ) -alkylene-NH 2 , 3) - (C 1 -C 6 ) -alkylene-NH-C (= NH) -NH 2 ,
4) -(C1-C6)-Alkylen-NH-C(=NH)-(C1-C4)-Alkyl,4) - (C 1 -C 6 ) -alkylene-NH-C (= NH) - (C 1 -C 4) -alkyl,
5) -(C0-C4)-Alkylen-O-NH-C(=NH)-NH2,5) - (C 0 -C 4 ) -alkylene-O-NH-C (= NH) -NH 2 ,
6) -(C0-C4)-Alkylen-NH-C(O)-(C-i -C6)-Alkyl, 7) -(Ci-C6)-Alkylen-NH-C(O)-O-(C1-C4)-Alkylen-Aryl, wobei Aryl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist,6) - (C 0 -C 4) -alkylene-NH-C (O) - (C 1 -C 6 ) -alkyl, 7) - (C 1 -C 6 ) -alkylene-NH-C (O) -O- (C 1 -C 4 ) -alkylene-aryl, wherein aryl is unsubstituted or substituted by -NH 2 or by -NH 2 and one, two or is substituted by R15 in triplicate,
8) -(C3-C8)-Cycloalkyl-NH2, oder 9) -(Co-C4)-Alkylen-(Cg-Ci4)-Aryl, wobei Aryl unsubstituiert oder durch -8) - (C 3 -C 8) -cycloalkyl-NH 2 , or 9) - (C 1 -C 4) -alkylene- (C 1 -C 4) -aryl, where aryl is unsubstituted or substituted by
NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist, steht, R3 für 1) -(C-|-C6)-Alkyl,NH 2 is substituted by -NH 2 and monosubstituted, disubstituted or trisubstituted by R 15, R 3 is 1) - (C 1 -C 6) -alkyl,
2) -(Cn-C4)-Alkylen-(C3-C-|2)-Cycloalkyl, 3) -(C-|-C6)-Alkylen-(C6-C-j4)-Aryl, wobei Aryl unabhängig voneinander ein-2) - (Cn-C4) -alkylene- (C3-C- | 2 ) -cycloalkyl, 3) - (C-C6) -alkylene- (C6-C-j4) -aryl, wherein aryl is independently -
, zwei- oder dreifach durch R15 substituiert ist,, is substituted two or three times by R 15,
4) -(C0-C8)-A[kylen-N(R5)-PG,4) - (C 0 -C 8 ) -alkylene-N (R 5) -PG,
5) -(C i-C6)-Alkylen-N H-C(O)-O-(C -i -C4)-Alkylen-Aryl, wobei Aryl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist, 6) -(Co-C4)-Alkylen-(C6-Ci4)-Aryl-(Co-C4)-Alkylen-N(R5)-PG,5) - (C 1 -C 6) -alkylene-N HC (O) -O- (C 1 -C 4) -alkylene-aryl, where aryl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15, 6) (C 1 -C 4 ) -alkylene- (C 6 -C 14) -aryl (C 1 -C 4 ) -alkylene-N (R 5) -PG,
7) -(C0-C8)-Alkylen-O-PG,7) - (C 0 -C 8 ) -alkylene-O-PG,
8) -(Co-C4)-A!kylen-(C6-Ci4)-Aryl-(Co-C4)-Alkylen-O-PG,8) - (Co-C4) -alkylene- (C6-C14) -aryl (Co-C4) -alkylene-O-PG,
9) -(C0-C8)-Alkylen-C(O)-O-PG,9) - (C 0 -C 8 ) -alkylene C (O) -O-PG,
10) -(Co-C4)-Alkylen-(C6-C14)-Aryl-(Co-C4)-Alkylen-C(O)-O-PG oder 11) Wasserstoff atonn, steht,10) - (Co-C 4 ) -alkylene- (C 6 -C 14 ) -aryl (Co-C 4 ) -alkylene-C (O) -O-PG or 11) hydrogen atonn,
R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander fürR4 is -N (R6) 2, wherein R6 are the same or different and independently of one another
1) Wasserstoffatom,1) hydrogen atom,
2) -(C1-Ce)-AIkVl, 3) -(Cn-C4)-Alkylen-(C3-C<|2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R11 , Halogen, -C(O)-O-RH , -(C-|-C4)-Alkyl-O-R11 oder -O-(C-|-C4)-Alkyl substituiert ist, 4) -(Co-Cg)-Alkylen-(C6-C-|4)-Aryl, wobei Aryl und Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R11 , Halogen, -C(O)-O-RH , -(C-i-C^-Alkyl-O-RH , -C(O)-N(R8)2 oder2) - (C 1 -Ce) -AlkVl, 3) - (Cn-C4) -alkylene- (C3-C <| 2) -cycloalkyl, wherein cycloalkyl unsubstituted or independently of one, two, three or four times is substituted by R 11, halogen, -C (O) -O-RH, - (C 1 -C 4) -alkyl-O-R 11 or -O- (C 1 -C 4) -alkyl, 4) - (Co-Cg) -alkylene- (C6-C- | 4) -aryl, wherein aryl and alkylene are unsubstituted or independently of one another once, twice, three or four times by R11, halogen, -C (O) -O-RH, - (CiC ^ alkyl-O-RH, -C (O) -N (R8) 2 or
-O-(Ci-C4)-Alkyl substituiert sind, 5) -(C0-C8)-Alkylen-N(R5)-PG,-O- (C 1 -C 4) -alkyl, 5) - (C 0 -C 8) -alkylene-N (R 5) -PG,
6) -(Co-C4)-Alkylen-(C6-C14)-Aryl-(Co-C4)-Alkyl-N(R5)-PG,6) - (Co-C4) alkylene- (C6-C14) aryl (Co-C4) alkyl-N (R5) -PG,
7) -(C0-C8)-Alkylen-O-PG,7) - (C 0 -C 8) -alkylene-O-PG,
8) -(C0-C4)-Alkylen-(C6-C14)-Aryl-(Co-C4)-Alkyl-O-PG,8) - (C 0 -C 4) -alkylene- (C 6 -C 14 ) -aryl (Co-C 4 ) -alkyl-O-PG,
9) -(C0-C8)-Alkylen-C(O)-O-R11 , 10) -(C0-C4)-Alkylen-(C6-C>i4)-Aryl-(Co-C4)-Alkyl-C(O)-O-PG,9) - (C 0 -C 8) -alkylene-C (O) -O-R11, 10) - (C0-C4) alkylene- (C6-C> i4) aryl (Co-C4) - alkyl-C (O) -O-PG,
11) -(Co-C4)-Alkylen-Het, wobei unter Het ein 4- bis 15-gliedriges heterocyclisches Ringsystem verstanden wird mit 4 bis 15 Ringatomen, die in ein, zwei oder drei miteinander verbundenen Ringsystemen vorliegen und die ein, zwei, drei oder vier gleiche oder verschiedene Heteroatome aus der Reihe Sauerstoff, Stickstoff oder Schwefel enthalten, wobei Het oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-RH , -(C<|-C4)-Alkyl-O-R11 oder -O-(C<|-C4)-Alkyl substituiert sind,11) - (Co-C4) -alkylene-Het, where Het is a 4- to 15-membered heterocyclic ring system is understood with 4 to 15 ring atoms, which are present in one, two or three interconnected ring systems and the one, two, contain three or four identical or different heteroatoms from the series oxygen, nitrogen or sulfur, wherein Het or alkylene is unsubstituted or independently of one another once, twice or three times by R11, halogen, -C (O) -O-RH, - (C <C 1 -C 4 ) -alkyl-O-R 11 or -O- (C 1 -C 4 ) -alkyl,
12) -(C-i-C3)-Fluoralkyl, 13) -(C0-C4)-Alkylen-CH(R11)-C(O)-NH2,12) - (C 1 -C 3 ) -fluoroalkyl, 13) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH 2,
14) -(C0-C4)-Alkylen-CH(R11)-C(O)-NH-(C <|-C4)-Alkyl,14) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH- (C 1 -C 4 ) -alkyl,
15) -(C0-C4)-Alkylen-CH(R11 )-C(O)-NH-CH(R12)-R13, oder15) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH-CH (R 12) -R 13, or
16) Aminosäure, wobei die Bindung der Aminosäure über eine Peptid- Bindung erfolgt und der Carboxyl-Rest der Aminosäure unsubstituiert oder durch PG oder durch -N(R5)2 substituiert ist, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom, an das sie gebunden sind, einen mono- oder bicyclischen Ring mit 4 bis 9 Ringatomen bilden, der gesättigt, teilweise gesättigt oder aromatisch ist, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(C-|-C4)-Alkyl, -C(O)-O-R11 , Halogen, -(C-|-C4)-Alkyl-O-R11 oder Phenyl substituiert ist, R5 für Wasserstoffatom oder-(C-j-Cg)-Alkyl steht,16) amino acid, wherein the binding of the amino acid takes place via a peptide bond and the carboxyl radical of the amino acid is unsubstituted or substituted by PG or by -N (R5) 2, or the two radicals R6 together with the N-atom to which they are attached form a mono- or bicyclic ring having 4 to 9 ring atoms which is saturated, partially saturated or aromatic, the ring being unsubstituted or mono- or disubstituted by - (C 1 -C 4) -alkyl, -C (O) -O-R11, halogen, - (C- | -C4) -alkyl-O-R11 or phenyl is substituted, R5 is hydrogen or (Cj-Cg) alkyl,
PG füreine Schutzgruppe für die Amino-, Carboxyl- oder für die Hydroxyfunktion steht, R7 für Wasserstoffatom oder -(C-j-C6)-Alkyl steht,PG is a protective group for the amino, carboxyl or for the hydroxyl function, R 7 is hydrogen atom or - (C 1 -C 6) -alkyl,
R8 für Wasserstoffatom oder -(C-|-C6)-Alkyl steht, R9 für Wasserstoffatom oder -(C 1 -CßJ-Aikyl steht,R 8 is hydrogen or - (C 1 -C 6) -alkyl, R 9 is hydrogen or - (C 1 -CβJ -acyl,
R11 und R12 gleich oder verschieden sind und unabhängig voneinander fürR11 and R12 are the same or different and independently of each other
1) Wasserstoff atom,1) hydrogen atom,
2) -(C1-C6JnAIlCyI,2) - (C 1 -C 6 -alkynyl,
3) -(Cn-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch Halogen, -OH oder3) - (Cn-C4) -alkylene-phenyl, wherein phenyl unsubstituted or independently of one another once, twice or three times by halogen, -OH or
-O-(C-|-C4)-Alkyl substituiert ist,-O- (C 1 -C 4) -alkyl is substituted,
4) -(Co-C4)-Alkylen-(C3-C-j2)-Cycloa!kyl, wobei Cycloaikyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R13, Halogen, -C(O)-O-R13, -(Ci-C4)-Alkyl-O-R13, -O-(C-|-C4)-Alkyl oder -(Co-C4)-Alkylen-Phenyl substituiert ist,4) - (Co-C4) -alkylene- (C3-C-j2) -cycloalkyl, where cycloalkyl is unsubstituted or independently of one another once, twice, three or four times by R13, halogen, -C (O) - O-R 13, - (C 1 -C 4) -alkyl-O-R 13, -O- (C 1 -C 4) -alkyl or - (C 0 -C 4) -alkylene-phenyl,
5) -(C0-C4)-Alkylen-C(O)-N(R13)2 oder5) - (C 0 -C 4 ) -alkylene-C (O) -N (R 13) 2 or
6) -(Cn-C4)-Alkylen-Indolyl, stehen, R13 für 1 ) Wasserstoffatom,6) - (C 1 -C 4) -alkylene-indolyl, R 13 is 1) hydrogen,
2) -(C1-C4)-Alkyl, 3) -(Cn-C4)-Alkylen-C(O)-O-R14,2) - (C 1 -C 4) -alkyl, 3) - (Cn-C4) -alkylene-C (O) -O-R14,
4) -(C0-C4)-Alkylen-C(O)-R14 oder4) - (C 0 -C 4 ) -alkylene-C (O) -R 14 or
5) -(Cn-C4)-Alkylen-O-R14 steht,5) - (Cn-C4) -alkylene-O-R14,
R14 für Wasserstoffatom, -(C-|-C4)-Alkyl, -NH2 oder -OH, steht und R15 für Wasserstoffatom, -(C-|-C4)-Alkyl, -0-CF3, -NH2, -OH, -CF3 oder Halogen steht.R 14 is hydrogen, - (C 1 -C 4 ) -alkyl, -NH 2 or -OH, and R 15 is hydrogen, - (C 1 -C 4 ) -alkyl, -O-CF 3 , -NH 2, -OH , -CF3 or halogen.
Die Erfindung betrifft auch die Verwendung der Verbindung der Formel I, wobei X für -C(O)- steht.The invention also relates to the use of the compound of formula I wherein X is -C (O) -.
Die Erfindung betrifft auch die Verwendung der Verbindung der Formel I, wobei X für -SO2- steht.The invention also relates to the use of the compound of formula I, wherein X stands for -SO 2 -.
Die Erfindung betrifft auch die Verwendung der Verbindung der Formel I, wobei X für -C(O)- steht, R1 für 1) Wasserstoffatom oder 2) -(Ci-C4)-Alkyl, steht,The invention also relates to the use of the compound of the formula I in which X is -C (O) -, R 1 is 1) hydrogen or 2) - (C 1 -C 4) -alkyl,
R2 für 1) -(C1-C6)-Alkylen-NH2,R 2 for 1) - (C 1 -C 6 ) -alkylene-NH 2 ,
2) -(Co-C4)-Alkylen-Pyridyl-NH2,2) - (Co-C4) -alkylene-pyridyl-NH 2 ,
3) -(Crj-C4)-Alkylen-Piperidinyl-NH2, 4) -(Co-C4)-Alkylen-Thiazolyl-NH2,3) - (Crj-C4) -alkylene-piperidinyl-NH 2 , 4) - (Co-C 4 ) -alkylene-thiazolyl-NH 2 ,
5) -(C1-C6)-Alkylen-NH-C(=NH)-NH2,5) - (C 1 -C 6 ) -alkylene-NH-C (= NH) -NH 2 ,
6) -(C0-C4)-Alky!en-(C3-C8)-Cyc!oalkyl-NH2,6) - (C 0 -C 4 ) -alkyl (C 3 -C 8 ) -cycloalkyl-NH 2,
7) -(Ci-C6)-Alkylen-NH-C(=NH)-(C-|-C4)-Alkyl,7) - (C 1 -C 6) -alkylene-NH-C (NHNH) - (C 1 -C 4) -alkyl,
8) -(C0-C4)-Alkylen-O-NH-C(=NH)-NH2i 9) -(C 1-C6)-Alkylen-N H-C(O)-O-(C -i -C4)-Alkylen-Aryl, wobei Aryl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist,8) - (C 0 -C 4 ) -alkylene-O-NH-C (= NH) -NH 2i 9) - (C 1 -C 6 ) -alkylene-N HC (O) -O- (C-i -C 4 ) -alkylene-aryl, wherein aryl is unsubstituted or substituted by -NH 2 or substituted by -NH 2 and mono-, di- or trisubstituted by R 15,
10) -(C0-C4)-Alkylen-N H-C(O)-(C 1 -C4)-Alkyl,10) - (C 0 -C 4 ) -alkylene-N HC (O) - (C 1 -C 4 ) -alkyl,
11) -(Crj-C4)-Alkylen-(C6-C-|4)-Aryl, wobei Aryl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist, oder11) - (Crj-C4) -alkylene- (C6-C- | 4) -aryl, wherein aryl is unsubstituted or substituted by -NH2 or substituted by -NH2 and mono-, di- or trisubstituted by R15, or
12) -(C<|-C4)-Alkylen-SOx-(C-|-C4)-Alkylen-NH2 worin x die ganze Zahl Null,12) - (C 1-C 4) -alkylene-SO x - (C 1 -C 4) -alkylene-NH 2 where x is the integer zero,
1 oder 2 bedeutet, steht, R3 für 1) -(C-|-C4)-Alkyl, 2) -(C0-C4)-Alkylen-(C3-C8)-Cycloalkyl,1 or 2, R 3 is 1) - (C 1 -C 4 ) -alkyl, 2) - (C 0 -C 4 ) -alkylene- (C 3 -C 8) -cycloalkyl,
3) -(C-|-C6)-Alkylen-Aryl, wobei Aryl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,3) - (C 1 -C 6) -alkylene-aryl, where aryl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15,
4) -(Ci-C6)-Alkylen-NH-C(O)-O-(C1-C4)-Alkylen-Aryl, wobei Aryl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist, 5) -(C-i-CßJ-Alkylen-NH-PG,4) - (C 1 -C 6 ) -alkylene-NH-C (O) -O- (C 1 -C 4 ) -alkylene-aryl, where aryl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15, 5) - (Ci-CβJ-alkylene-NH-PG,
6) -(C«|-C6)-Alkylen-0-PG,6) - (C "| C6) alkylene-0-PG,
7) -(C-i-C6)-Alkyl, oder7) - (CiC 6 ) alkyl, or
8) Wasserstoffatom, steht, wobei PG für t-Butyl-, t-Butyloxycarbonyl oder Benzyloxycarbonyl steht,8) hydrogen, where PG is t-butyl, t-butyloxycarbonyl or benzyloxycarbonyl,
R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander fürR4 is -N (R6) 2, wherein R6 are the same or different and independently of one another
1 ) Wasserstoffatom ,1) hydrogen atom,
2) -(C1-Ce)-AIRyI, 3) -(Crj-C4)-Alkylen-(C3-C-|2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R11 , Halogen, -C(O)-O-RH, -(C-|-C4)-Alkyl-O-R11 oder -O-(C-j-C4)-Alkyl substituiert ist,2) - (C 1 -Ce) -AIRyl, 3) - (C 1 -C 4) -alkylene- (C 3 -C 12) -cycloalkyl, where cycloalkyl is unsubstituted or independently of one, two, three or four times is substituted by R 11, halogen, -C (O) -O-RH, - (C 1 -C 4) -alkyl-O-R 11 or -O- (C 1 -C 4) -alkyl,
4) -(C0-C4)-A!kylen-C(R11)(R12)-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch4) - (C 0 -C 4 ) -alkylene-C (R 11) (R 12) - (C 3 -C 12) -cycloalkyl, where cycloalkyl is unsubstituted or independently mono-, di- or trihydric
R11 , Halogen, -C(O)-O-RH , -(C<|-C4)-Alkyl-O-R11 oder -0-(C1 -C4)-Alkyl substituiert ist,R11, halogen, -C (O) -O-RH, - (C <~C 4 ) -alkyl-O-R11 or -O- (C 1 -C 4 ) -alkyl,
5) -(Cn-C4)-Alkylen-Het, wobei unter Het ein 4- bis 15-gliedriges heterocyclisches Ringsystem verstanden wird mit 4 bis 15 Ringatomen, die in ein, zwei oder drei miteinander verbundenen Ringsystemen vorliegen und die ein, zwei, drei oder vier gleiche oder verschiedene Heteroatome aus der Reihe Sauerstoff, Stickstoff oder Schwefel enthalten, wobei Het oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-RH , -(C<|-C4)-Alkyl-O-R11 oder -0-(C1 -C4)-Alkyl substituiert sind,5) - (Cn-C4) -alkylene-Het, where Het is a 4- to 15-membered heterocyclic ring system is understood with 4 to 15 ring atoms, which are present in one, two or three interconnected ring systems and the one, two, contain three or four identical or different heteroatoms from the series oxygen, nitrogen or sulfur, wherein Het or alkylene is unsubstituted or independently of one another once, twice or three times by R11, halogen, -C (O) -O-RH, - (C <C 1 -C 4 ) -alkyl-O-R 11 or -O- (C 1 -C 4 ) -alkyl,
6) -(Co-C6)-Alkylen-Aryl, wobei Aryl oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-R11 , -(C0-C4)-Alkyl-O-R11 oder -O-(C -i-C^-Alkyl substituiert sind,6) - (Co-C6) -alkylene-aryl, where aryl or alkylene are unsubstituted or independently of one another mono-, di- or trisubstituted by R11, halogen, -C (O) -O-R11, - (C 0 -C4) Alkyl-O-R11 or -O- (C 1 -C 4) -alkyl,
7) -(C0-C4)-Alkylen-C(R11 )(R12)-Aryl, wobei Aryl oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-RH , -(C0-C4)-Alkyl-O-R11 oder -0-(C1 -C4)-Alkyl substituiert sind,7) - (C 0 -C 4 ) -alkylene-C (R 11) (R 12) -aryl, wherein aryl or alkylene is unsubstituted or independently mono-, di- or trihydric R 11, halogen, -C (O) -O-RH, - (C 0 -C 4 ) -alkyl-O-R 11 or -O- (C 1 -C 4 ) -alkyl,
8) 1 ,2,3,4-Tetrahydro-naphthalenyl,8) 1, 2,3,4-tetrahydro-naphthalenyl,
9) -(Cn-C4)-Alkylen-CH(R11 )-C(O)-NH2, 10) -(Co-C4)-Alky!en-CH(R11 J-C(O)-NH-(C1 -C4)-Alkyl,9) - (Cn-C4) -alkylene-CH (R11) -C (O) -NH 2, 10) - (Co-C4) -Alky en-CH (R11 JC (O) -NH- (C 1 -C 4 ) -alkyl,
11) -(Co-C4)-Alkylen-CH(R11)-C(O)-NH-CH(R12)-R13,11) - (Co-C 4 ) -alkylene-CH (R 11) -C (O) -NH-CH (R 12) -R 13,
12) -(Crj-C6)-Alkylen-C(O)-O-R11 , wobei Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch R11 , Halogen, -C(O)-O-RH , -(C-i-C4)-Alkyl-O-R11 oder -0-(C1 -C4)-Alkyl substituiert ist, 13) -(Co-C4)-Alkylen-C(R11)(R12)-C(O)-O-R11 , oder12) - (Cr j -C 6) -alkylene-C (O) -O-R 11, where alkylene is unsubstituted or independently of one another once or twice by R 11, halogen, -C (O) -O-RH, - (CiC 4 ) -Alkyl-O-R11 or -O- (C 1 -C 4 ) -alkyl, 13) - (Co-C 4 ) -alkylene-C (R 11) (R 12) -C (O) -O- R11, or
14) -(C-i-CsJ-Fluoralkyl, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom, an das sie gebunden sind, einen mono- oder bicyclischen Ring mit 4 bis 9 Ringatomen bilden, der gesättigt, teilweise gesättigt oder aromatisch ist, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(C-i-C4)-Alkyl, -C(O)-O-R11 ,14) - (Ci-CsJ-fluoroalkyl, or the two radicals R6 together with the N-atom to which they are attached form a mono- or bicyclic ring having 4 to 9 ring atoms, which is saturated, partially saturated or aromatic where the ring is unsubstituted or mono- or disubstituted by - (C 1 -C 4 ) -alkyl, -C (O) -O-R 11,
Halogen, -(C1-C4)-AIkyl-O-R11 oder Phenyl substituiert ist, R7 für Wasserstoffatom oder -(C-i-C^-Alkyl steht, R9 für Wasserstoffatom oder -(C-|-C4)-Alkyl steht,Halogen, - (C 1 -C 4) -alkyl-O-R11 or phenyl, R7 is hydrogen atom or - (CiC ^ alkyl, R9 is hydrogen atom or - (C- | -C4) alkyl;
R11 und R12 gleich oder verschieden sind und unabhängig voneinander für 1) Wasserstoff atom,R 11 and R 12 are identical or different and independently of one another represent 1) hydrogen atom,
2) -(C1-C4)-Alkyl,2) - (C 1 -C 4 ) -alkyl,
3) -(Crj-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch Halogen, -OH oder -O-(C1-C4)-Alkyl substituiert ist, 4) -(Crj-C4)-Alkylen-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R13, Halogen, -C(O)-O-RI 3, -(Ci-C4)-Alkyl-O-R13, -O-^-C^-Alkyl oder3) - (Crj-C 4 ) -alkylene-phenyl, wherein phenyl is unsubstituted or independently of one another mono-, di- or trisubstituted by halogen, -OH or -O- (C 1 -C 4 ) -alkyl, 4) - (Cr j -C 4) -alkylene- (C3-Ci2) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently mono-, di-, tri- or four times by R13, halogen, -C (O) -O-RI 3 , - (C 1 -C 4 ) -alkyl-O-R 13, -O - ^ - C ^ -alkyl or
-(Co-C4)-A!kylen-Phenyl substituiert ist, 5) -(C0-C4)-Alkylen-C(O)-N(R13)2 oder 6) -(Co-C4)-Alkylen-Indolyl, stehen,- (Co-C 4 ) -A alkylene-phenyl is substituted, 5) - (C 0 -C 4 ) alkylene-C (O) -N (R 13) 2 or 6) - (Co-C4) -alkylene-indolyl,
R13 für 1) Wasserstoffatom,R 13 is 1) hydrogen,
2) -(Cϊ-C^-Alkyl,2) - (Cϊ-C ^ -alkyl,
3) -(C0-C4)-Alkylen-C(O)-O-R14, 4) -(Co-C4)-Alkylen-C(O)-R14 oder3) - (C 0 -C 4 ) -alkylene-C (O) -O-R 14, 4) - (Co-C 4) -alkylene-C (O) -R 14 or
5) -(Co-C4)-Alkylen-O-R14 steht,5) - (Co-C4) -alkylene-O-R14,
R14 für Wasserstoff atom, -(C 1 -C4J-AI kyl, -NH2 oder -OH, steht undR14 represents hydrogen atom, - (C 1 -C 4 -alkyl, -NH 2 or -OH, and
R15 für Wasserstoffatom, -(C-|-C4)-Alkyl, -0-CF3, -NH2, -OH, -CF3 oderR 15 is hydrogen, - (C 1 -C 4 ) -alkyl, -O-CF 3 , -NH 2 , -OH, -CF 3 or
Halogen steht.Halogen is available.
Die Erfindung betrifft auch die Verwendung der Verbindung der Formel I, wobei X für -C(O)- steht, R1 für 1) Wasserstoffatom oder 2) -(C1-C4)-Alkyl, steht, R2 für 1) -(C1-C6)-Alkylen-NH2,The invention also relates to the use of the compound of the formula I in which X is -C (O) -, R 1 is 1) hydrogen or 2) - (C 1 -C 4 ) -alkyl, R 2 is 1) - ( C 1 -C 6 ) -alkylene-NH 2 ,
2) -(Ci-C4)-Alkylen-Pyridyl-NH2,2) - (C 1 -C 4 ) -alkylene-pyridyl-NH 2,
3) -(C<|-C4)-Alkylen-Piperidinyl-NH2,3) - (C <| -C4) alkylene-piperidinyl-NH2,
4) -(C1-C6)-Alkylen-NH-C(=NH)-NH2,4) - (C 1 -C 6 ) -alkylene-NH-C (= NH) -NH 2 ,
5) -(C0-C4)-Alkylen-(C3-C6)-Cycloalkyl-NH2, 6) -(Ci-C6)-Alkylen-NH-C(=NH)-(C1-C4)-Alkyl,5) - (C 0 -C 4 ) -alkylene- (C 3 -C 6) -cycloalkyl-NH 2 , 6) - (C 1 -C 6) -alkylene-NH-C (NHNH) - (C 1 -C 4 ) alkyl,
7) -(C1-C4)-Alkylen-O-NH-C(=NH)-NH2i 7) - (C 1 -C 4 ) alkylene-O-NH-C (= NH) -NH 2i
8) -(Ci-C6)-Alkylen-NH-C(O)-O-(C1-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist, 9) -(Ci-C4)-Alkylen-NH-C(O)-(C1-C6)-Alkyl, oder8) - (C 1 -C 6 ) -alkylene-NH-C (O) -O- (C 1 -C 4 ) -alkylene-phenyl, where phenyl is unsubstituted or substituted independently of one another once, twice or three times by R 15 , 9) - (C 1 -C 4 ) -alkylene-NH-C (O) - (C 1 -C 6 ) -alkyl, or
10) -(C-)-C4)-Alkylen-Phenyl, wobei Phenyl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,10) - (C -) - C 4 ) -alkylene-phenyl, where phenyl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15,
11) -(Ci-C4)-Alkylen-SO2-(C1-C4)-Alkylen-NH2, oder11) - (Ci-C4) alkylene-SO 2 - (C 1 -C 4) alkylene-NH 2, or
12) -(C1-C4)-Alkylen-S-(C1-C4)-Alkylen-NH2, steht, R3 für 1) -(Ci-C4)-Alkyl,12) - (C 1 -C 4 ) -alkylene-S- (C 1 -C 4 ) -alkylene-NH 2 , R 3 is 1) - (C 1 -C 4) -alkyl,
2) -(Ci-C4)-Alkylen-(C3-C6)-Cycloalkyl,2) - (C 1 -C 4) -alkylene- (C 3 -C 6) -cycloalkyl,
3) -(C-i-C4)-Alkylen-Phenyi, wobei Phenyl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist,3) - (C 1 -C 4) -alkylene-phenylene, where phenyl is unsubstituted or substituted by -NH 2 or substituted by -NH 2 and mono-, di- or trisubstituted by R 15,
4) -(C-|-C6)-Alkylen-NH-C(O)-O-(Ci-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist,4) - (C 1 -C 6) -alkylene-NH-C (O) -O- (C 1 -C 4) -alkylene-phenyl, wherein phenyl is unsubstituted or substituted by -NH 2 or by -NH 2 and one, two or is substituted by R15 in triplicate,
5) Wasserstoffatom steht, R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander für5) is hydrogen, R4 is -N (R6) 2 , where R6 are the same or different and independently of one another
1) Wasserstoffatom,1) hydrogen atom,
2) -(Ci-C^-Alkyl,2) - (C 1 -C 4) -alkyl,
3) -(Co-C4)-Alkylen-(C3-C-|2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adaman- tanyl, Bicyclo[3.1.1]heptanyl, Decahydro-naphthalenyl, Tetrahydronaph-thalenyl, Octahydro-4,7-methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach substituiert ist durch -(C-i-C^-Alkyl, -C(O)-O-R11 oder -(C-i-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch Halogen substituiert ist,3) - (Co-C4) -alkylene- (C3-C- | 2) -cycloalkyl, where cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, bicyclo [3.1.1] heptanyl, decahydro -naphthalenyl, tetrahydronaphthalene, octahydro-4,7-methano-indenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently substituted once, twice, three or four times by - (C 1 -C 4 -alkyl , -C (O) -O-R11 or - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or substituted by halogen,
4) -(Co-C4)-Alkylen-C(R11)(R12)-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adamantanyl, Bicyclo[3.1.1]heptanyl, Decahydro-naphthalenyl, Tetrahydronaphthalenyl, Octahydro-4,7-methano-indenyl oder Bicyclo[2.2.1]- heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach substituiert ist durch -(C-|-C4)-Alkyl, -C(O)-O-R11 oder4) - (Co-C4) -alkylene-C (R11) (R12) - (C3-C12) -cycloalkyl, where cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, bicyclo [3.1.1] heptanyl, decahydro-naphthalenyl, tetrahydronaphthalenyl, octahydro-4,7-methanoindenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently of one another mono-, di-, tri- or tetra-substituted by - (C-) C 1 -C 4) -alkyl, -C (O) -O-R 11 or
-(C-|-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch Halogen substituiert ist, 5) -(Co-C4)-Alkylen-Het, wobei Het ausgewählt ist aus der Gruppe Acridinyl,- (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or substituted by halogen, 5) - (Co-C4) -alkylene-Het, wherein Het is selected from the group acridinyl,
Azepinyl, Azetidinyl, Aziridinyl, Benzimidazalinyl, Benzimidazolyl, Benzo[1 ,3]dioxolyl, Benzofuranyl, Benzothiofuranyl, Benzothiophenyl, Benzoxazolyl, Benzthiazolyl, Benztriazolyl, Benztetrazolyl, Benzisoxazolyl, Benzisothiazolyl, Carbazolyl, 4aH-Carbazolyl, Carbolinyl, Chinazolinyl,Azepinyl, azetidinyl, aziridinyl, benzimidazalinyl, benzimidazolyl, benzo [1,3] dioxolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl,
Chinolinyl, 4H-Chinolizinyl, Chinoxalinyl, Chinuclidinyl, Chromanyl, Chromenyl, Cinnolinyl, Deca-hydrochinolinyl, Dibenzofuranyl, Dibenzothiophenyl, Dihydrofuran[2,3-b]-tetrahydrofuranyl, Dihydrofuranyl, Dioxolyl, Dioxanyl, 2H1 6H-1,5,2-Dithiazinyl, Furanyl, Furazanyl, Imidazolidinyl, Imidazolinyl, Imidazolyl, 1 H-lndazolyl, Indolinyl, Indolizinyl, Indolyl, 3H-lndolyl, Isobenzofuranyl,Quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, deca-hydroquinolinyl, dibenzofuranyl, dibenzothiophenyl, dihydrofuran [2,3-b] tetrahydrofuranyl, dihydrofuranyl, dioxolyl, dioxanyl, 2H 1 6H-1,5,2 Dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,
Isochromanyl, Isoindazolyl, Isoindolinyl, Isoindolyl, Isochinolinyl (Benzimidazolyl), Isothiazolidinyl, 2-lsothiazolinyl, Isothiazolyl, Isoxazolyl, Isoxazolidinyl, 2-lsoxazolinyl, Morpholinyl, Naphthyridinyl, Octahydroisochinolinyl, Oxadiazolyl, 1 ,2,3-Oxadiazolyl, 1 ,2,4-Oxadiazolyl, 1 ,2,5- Oxadiazolyl, 1 ,3,4-Oxadiazolyl, Oxazolidinyl, Oxazolyl, Oxazolidinyl,Isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolidinyl, 2-isothiazolinyl, isothiazolyl, isoxazolyl, isoxazolidinyl, 2-isoxazolinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1, 2,3-oxadiazolyl, 1, 2,4 -Oxadiazolyl, 1, 2,5-oxadiazolyl, 1, 3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl,
Oxothiolanyl, Pyrimidinyl, Phenanthridinyl, Phenanthrolinyl, Phenazinyl, Phenothiazinyl, Phenoxathiinyl, Phenoxazinyl, Phthalazinyl, Piperazinyl, Piperidinyl, Pteridinyl, Purynyl, Pyranyl, Pyrazinyl, Pyroazolidinyl, Pyrazolinyl, Pyrazolyl, Pyridazinyl, Pryidooxazolyl, Pyridoimidazolyl, Pyridothiazolyl, Pyridothiophenyl, Pyridinyl, Pyridyl, Pyrimidinyl, Pyrrolidinyl, Pyrrolinyl, 2H-Oxothiolanyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridothiophenyl, pyridinyl, pyridyl, Pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-
Pyrrolyl, Pyrrolyl, Tetrahydrofuranyl, Tetrahydroisochinolinyl, Tetrahydrochinolinyl, Tetrahydropyridinyl, 6H-1 ,2,5-Thiadazinyl, 1 ,2,3- Thiadiazolyl, 1 ,2,4-Thiadiazolyl, 1 ,2,5-Thiadiazolyl, 1 ,3,4-Thiadiazolyl, Thianthrenyl, Thiazolyl, Thienyl, Thienoimidazolyl, Thienooxazolyl, Thienopyridin, Thienothiazolyl, Thiomorpholinyl, Thiophenyl, Triazinyl, 1 ,2,3-Pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl, 6H-1, 2,5-thiadazinyl, 1, 2,3-thiadiazolyl, 1, 2,4-thiadiazolyl, 1, 2,5-thiadiazolyl, 1, 3, 4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienoimidazolyl, thienooxazolyl, thienopyridine, thienothiazolyl, thiomorpholinyl, thiophenyl, triazinyl, 1, 2,3-
Triazolyl, 1 ,2,3-Triazolyl, 1 ,2,4-Triazolyl, 1 ,2,5-Triazolyl, 1 ,3,4-Triazolyl und Xanthenyl, wobei Het oder Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch -(C-|-C4)-Alkyl substituiert istTriazolyl, 1, 2,3-triazolyl, 1, 2,4-triazolyl, 1, 2,5-triazolyl, 1, 3,4-triazolyl and xanthenyl, wherein Het or alkylene is unsubstituted or independently of one another or by - (C 1 -C 4) alkyl is substituted
6) -(C-|-C6)-Alkylen-Phenyl, wobei Phenyl oder Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Halogen, Phenyl,6) - (C 1 -C 6) -alkylene-phenyl, where phenyl or alkylene is unsubstituted or independently of one another by halogen, phenyl,
-C(O)-O-RH , -(Ci-C4)-Alkyl-O-R11 , -O-(C<|-C4)-Alkyl oder -^-C^-Alkyl substituiert sind, 7) -(Co-C4)-Alkylen-C(R11)(R12)-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch Phenyl oder Fluor substituiert ist,-C (O) -O-H, - (Ci-C4) -alkyl-O-R11, -O- (C <| -C4) alkyl or - ^ - C ^ alkyl substituted, 7) - (Co-C4) -alkylene-C (R11) (R12) -phenyl, where phenyl is unsubstituted or independently of one another mono-, di- or trisubstituted by phenyl or fluorine,
8) 1 ,2,3,4-Tetrahydro-naphthalenyl, 9) -(C0-C4)-Alkylen-CH(R11)-C(O)-NH2,8) 1, 2,3,4-tetrahydro-naphthalenyl, 9) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH 2 ,
10) -(C0-C4)-Alkylen-CH(R11)-C(O)-N H-(Ci -C4)-Alkyl,10) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -N H- (C 1 -C 4 ) -alkyl,
11 ) -(C0-C4)-Alkylen-CH(R11 )-C(O)-NH-CH(R12)-R13,11) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH-CH (R 12) -R 13,
12) -(C-|-C6)-Alkylen-C(O)-O-R11 , wobei Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Halogen, Phenyl, -C(O)-O-RH , -(C-|-C4)-Alkyl-O-R11 , -O-(Ci-C4)-Alkyl oder -(C-|-C4)-Alkyl substituiert ist,12) - (C 1 -C 6) alkylene-C (O) -O-R 11, wherein alkyls are unsubstituted or independently of one another by halogen, phenyl, -C (O) -O-RH, - (C - | -C4) alkyl-O-R11, -O- (Ci-C 4) -alkyl or - (C- | -C4) alkyl is substituted,
13) -(C0-C4)-Alkylen-C(R11)(R12)-C(O)-O-R11 , oder13) - (C 0 -C 4 ) -alkylene-C (R 11) (R 12) -C (O) -O-R 11, or
14) -(C-|-C3)-Fluoralkyl, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom an das sie gebunden sind einen Mono- oder Bicyclischen Ring bilden ausgewählt aus der Gruppe14) - (C 1 -C 3) -fluoroalkyl, or the two radicals R 6 together with the N-atom to which they are attached form a mono- or bicyclic ring selected from the group
Pyrrolidin, Piperidin, 2-Aza-bicyclo[3.2.2]nonan und 7-Aza-bicyclo[2.2.1]hep-tan, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(Ci-C4)-Alkyl, -Pyrrolidine, piperidine, 2-azabicyclo [3.2.2] nonane and 7-azabicyclo [2.2.1] heptene, the ring being unsubstituted or mono- or disubstituted by (C 1 -C 4 ) -alkyl, -
C(O)-O-RH , -(C«|-C4)-Alkyl-O-R11 oder Phenyl substituiert ist, R7 für Wasserstoffatom oder -(C-|-C4)-Alkyl steht, R9 für Wasserstoff atom oder -(C-|-C4)-Alkyl steht,Is substituted alkyl-O-R11 or phenyl, R7 is hydrogen atom or - (C- | -C4) | (-C 4 C ") - C (O) -O-RH, is alkyl, R9 is hydrogen atom or - (C 1 -C 4 ) -alkyl,
R11 und R12 gleich oder verschieden sind und unabhängig voneinander fürR11 and R12 are the same or different and independently of each other
1) Wasserstoffatom,1) hydrogen atom,
2) -(Ci-C^-Alkyl,2) - (C 1 -C 4) -alkyl,
3) -(Crj-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch -OH, Halogen oder3) - (Crj-C 4 ) -alkylene-phenyl, wherein phenyl unsubstituted or independently of one another once, twice or three times by -OH, halogen or
-O-(C<|-C4)-Alkyl substituiert ist,-O- (C 1 -C 4 ) -alkyl is substituted,
4) -(Co-C4)-Alkylen-(C3-C-|2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adaman- tanyl, Bicyclo[3.1.1]heptanyl, Octahydro-4,7-methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch -(C-|-C4)-Alkyl,4) - (Co-C 4 ) -alkylene- (C 3 -C 12) -cycloalkyl, where cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, bicyclo [3.1.1] heptanyl, Octahydro-4,7-methanoindenyl or bicyclo [2.2.1] heptanyl and wherein cycloalkyl is unsubstituted or independent one, two, three or four times by - (C 1 -C 4) -alkyl,
-C(O)-O-RI 3 oder Phenyl substituiert ist, oder 5) -(Cn-C4)-Alkylen-Indolyl, stehen,-C (O) -O-RI 3 or phenyl, or 5) - (Cn-C4) -alkylene-indolyl,
R13 für 1 ) Wasserstoffatom, 2) -(C-|-C4)-Alkyl,R 13 is 1) hydrogen, 2) - (C 1 -C 4) -alkyl,
3) -(Crj-C4)-Alkylen-C(O)-O-R14,3) - (Crj-C4) -alkylene-C (O) -O-R14,
4) -(C0-C4)-Alkylen-C(O)-R14 oder4) - (C 0 -C 4 ) -alkylene-C (O) -R 14 or
5) -(Cn-C4)-Alkylen-O-R14 steht, und5) - (Cn-C4) -alkylene-O-R14, and
R14 für Wasserstoffatom, -(C-i-C4)-Alkyl, -NH2 oder -OH steht und R15 für Wasserstoffatom, -(C-j-C4)-Alkyl, -O-CF3, -NH2, -OH, -CF3 oder Halogen steht.R 14 is hydrogen, - (C 1 -C 4 ) -alkyl, -NH 2 or -OH and R 15 is hydrogen, - (C 1 -C 4 ) -alkyl, -O-CF 3, -NH 2, -OH, -CF 3 or halogen.
Die Erfindung betrifft auch die Verwendung der Verbindung der Formel I, wobei X für -C(O)- steht, R1 für 1) Wasserstoffatom oder 2) -(C1 -C4)-Alkyl, steht,The invention also relates to the use of the compound of the formula I in which X is -C (O) -, R 1 is 1) hydrogen or 2) - (C 1 -C 4) -alkyl,
R2 für 1) -(C1-C6)-Alkylen-NH2,R 2 for 1) - (C 1 -C 6 ) -alkylene-NH 2 ,
2) -(C<|-C4)-Alkylen-Pyridyl-NH2,2) - (C <| -C4) alkylene-pyridyl-NH2,
3) -(C-j-C4)-Alkylen-Piperidinyl-NH2, 4) -(C1-C4)-Alkylen-NH-C(=NH)-NH2,3) - (C 1 -C 4 ) -alkylene-piperidinyl-NH 2 , 4) - (C 1 -C 4 ) -alkylene-NH-C (= NH) -NH 2 ,
5) -(C1-C6)-Alkylen-NH-C(=NH)-(C1-C4)-Alkyl,5) - (C 1 -C 6 ) -alkylene-NH-C (= NH) - (C 1 -C 4 ) -alkyl,
6) -(C1-C4)-Alkylen-(C3-C6)-Cycloalkyl-NH2,6) - (C 1 -C 4 ) -alkylene- (C 3 -C 6 ) -cycloalkyl-NH 2 ,
7) -(C1-C4)-Alkylen-O-NH-C(=NH)-NH2i 7) - (C 1 -C 4) alkylene-O-NH-C (= NH) -NH 2i
8) -(C1-C6)-Alkylen-NH-C(O)-O-(C1-C4)-Alkylen-Phenyl, 9) -(C1-C4)-Alkylen-NH-C(O)-(Ci-C6)-Alkyl,8) - (C 1 -C 6 ) -alkylene-NH-C (O) -O- (C 1 -C 4 ) -alkylene-phenyl, 9) - (C 1 -C 4 ) -alkylene-NH-C ( O) - (C 1 -C 6 ) -alkyl,
10) -(C1-C4)-Alkylen-Phenyl-NH2,10) - (C 1 -C 4 ) -alkylene-phenyl-NH 2,
11) -(C1-C2)-Alkylen-SO2-(C1-C4)-Alkylen-NH2, oder11) - (C 1 -C 2 ) -alkylene-SO 2 - (C 1 -C 4 ) -alkylene-NH 2 , or
12) -(C1-C2)-Alkylen-S-(Ci-C4)-Alkylen-NH2, steht, R3 für 1) -(C-i-C^-Alkyl, 2) -(C1-C4)-Alkylen-(C3-C6)-Cycloalkyl,12) - (C 1 -C 2 ) -alkylene-S- (C 1 -C 4 ) -alkylene-NH 2 , R 3 is 1 ) - (C 1 -C 4 -alkyl) 2) - (C 1 -C 4) -alkylene- (C 3 -C 6 ) -cycloalkyl,
3) -(C-|-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch -OH substituiert ist,3) - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or substituted by -OH,
4) -(C1 -C6)-A!kylen-N H-C(O)-O-(C -| -C4)-Alkylen-Pheny I , 5) Wasserstoffatom steht,4) - (C 1 -C 6) -alkylene-N HC (O) -O- (C 1 -C 4 ) -alkylene-pheny I, 5) is hydrogen atom,
R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander fürR4 is -N (R6) 2, wherein R6 are the same or different and independently of one another
1 ) Wasserstoffatom ,1) hydrogen atom,
2) -(C^C^-Alkyl, 3) -(Co-C4)-Alkylen-(C3-C8)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclopropyl, Adamantanyl, 1 ,7,7- Trimethyl-bicyclo[3.1.1]heptanyl, Tetrahydro-naphthalenyl, Decahydro- naphthalenyl, Octahydro-4,7-methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch -(C-|-C4)-Alkyl oder Pheny! substituiert ist,2) - (C 1 -C 4 alkyl, 3) - (C 0 -C 4) alkylene- (C 3 -C 8) cycloalkyl, wherein cycloalkyl is selected from the group consisting of cyclohexyl, cyclopentyl, cyclopropyl, adamantanyl, 1, 7, 7 - Trimethyl-bicyclo [3.1.1] heptanyl, tetrahydro-naphthalenyl, decahydro-naphthalenyl, octahydro-4,7-methano-indenyl or bicyclo [2.2.1] heptanyl and wherein cycloalkyl unsubstituted or independently of one another once, twice or three times by - (C 1 -C 4) -alkyl or pheny! is substituted,
4) -C(R11)(R12)-Adamantanyl,4) -C (R11) (R12) adamantanyl,
5) -CH(RI 1)-C(O)-NH-CH(R12)-R13,5) -CH (RI 1) -C (O) -NH-CH (R 12) -R 13,
6) -(Cn-C4)-Alkylen-Het, wobei Het ausgewählt ist aus der Gruppe6) - (Cn-C4) -alkylene-Het, wherein Het is selected from the group
Benzimidazolyl, Isoxazolyl, Piperidinyl, Pyridinyl, Pyrrolidinyl, Thiophenyl und Benzo[1 ,3]dioxolyl,Benzimidazolyl, isoxazolyl, piperidinyl, pyridinyl, pyrrolidinyl, thiophenyl and benzo [1,3] dioxolyl,
7) 1 ,2,3,4-Tetrahydro-naphthalenyl,7) 1, 2,3,4-tetrahydro-naphthalenyl,
8) -(Cn-C4)-Alkylen-C(R11 )(R12)-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch Phenyl oder Fluor substituiert ist, 9) -CH(RH)-C(O)-NH2,8) - (Cn-C4) -alkylene-C (R11) (R12) -phenyl, wherein phenyl is unsubstituted or independently mono-, di- or trisubstituted by phenyl or fluorine, 9) -CH (RH) -C (O) -NH 2 ,
10) -CH(RI 1)-C(O)-NH-CH(R12)-CH2-OH,10) -CH (RI 1) -C (O) -NH-CH (R 12) -CH 2 -OH,
11) -(C-|-C6)-Alkylen-Phenyl, wobei Phenyl oder Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Chlor, Fluor, -C(O)-O-RH , -(C1-C4)-Alkyl-O-R11 , -O-(C<|-C4)-Alkyl, Phenyl oder -(C-|-C4)-Alkyl substituiert sind, 12) -CH(RI I)-C(O)-NH-(C1 -C4)-Alkyl,11) - (C 1 -C 6) -alkylene-phenyl, where phenyl or alkylene is unsubstituted or independently of one another by chlorine, fluorine, -C (O) -O-RH, - (C 1 -C 4 ) Alkyl-O-R 11, -O- (C 1 -C 4 ) -alkyl, phenyl or - (C 1 -C 4 ) -alkyl, 12) -CH (RI 1) -C (O) -NH- (C 1 -C 4 ) -alkyl,
13) -(Co-C4)-Alkylen-C(R11 )(R12)-Bicyclo[3.1.1 ]heptanyl, wobei13) - (Co-C4) -alkylene-C (R11) (R12) -bicyclo [3.1.1] heptanyl, wherein
Bicyclo[3.1.1]heptanyl unsubstituiert oder ein- bis vierfach durch -(C-|-C4)-Alkyl substituiert ist, 14) -(Ci-C6)-Alkylen-C(O)-O-R11 , wobei Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Chlor, Fluor, -C(O)-O-RH , - (C-|-C4)-Alkyl-O-R11 , -O-(Ci-C4)-Alkyl, Phenyl oder -(C-|-C4)-Alkyl substituiert ist,Bicyclo [3.1.1] heptanyl is unsubstituted or substituted one to four times by - (C 1 -C 4) -alkyl; 14) - (C 1 -C 6) -alkylene-C (O) -O-R 11, where alkylene is unsubstituted or independently of one another by chlorine, fluorine, -C (O) -O-RH, - (C-C4) -alkyl-O-R11, -O- (Ci-C4) alkyl, phenyl or - (C 1 -C 4) -alkyl is substituted,
15) -(C0-C4)-Alkylen-C(R11 )(R12)-C(O)-O-R11 , oder 16) -CH2-CF2-CF3, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom an das sie gebunden sind einen Mono- oder Bicyclischen Ring bilden, ausgewählt aus der Gruppe Pyrrolidine, 2-aza-bicyclo[3.2.2]nonan und 7-aza-bicyclo[2.2.1]heptan, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(C-|-C4)-Alkyl, -C(O)-O-R11 , -(Ci-C4)-Alkyl-O-R11 oder Phenyl substituiert ist,15) - (C 0 -C 4 ) -alkylene-C (R 11) (R 12) -C (O) -O-R 11, or 16) -CH 2 -CF 2 -CF 3, or the two radicals R 6 together with the N-atom to which they are attached form a mono- or bicyclic ring selected from the group consisting of pyrrolidines, 2-aza-bicyclo [3.2.2] nonane and 7-aza-bicyclo [2.2.1] heptane, the ring being unsubstituted or is monosubstituted or disubstituted by - (C 1 -C 4) -alkyl, -C (O) -O-R 11, - (C 1 -C 4) -alkyl-O-R 11 or phenyl,
R7 für Wasserstoffatom oder -(Ci-C4)-Alkyl steht, R9 für Wasserstoffatom oder -(C<|-C4)-Alkyl steht,R 7 is hydrogen or - (C 1 -C 4) -alkyl, R 9 is hydrogen or - (C 1 -C 4) -alkyl,
R11 und R12 gleich oder verschieden sind und unabhängig voneinander fürR11 and R12 are the same or different and independently of each other
1) Wasserstoffatom, 2) -(C1-C4)-Alkyl,1) hydrogen, 2) - (C 1 -C 4 ) -alkyl,
3) -(Co-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch -OH, Halogen oder -O-(C-|-C4)-Alkyl substituiert ist,3) - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or independently of one another mono-, di- or trisubstituted by -OH, halogen or -O- (C 1 -C 4) -alkyl,
4) -(Co-C4)-Alkylen-(C3-C<| 2J-CyC1Oa1W. wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adaman- tanyl, 1 ,7,7-Trimethyl-bicyclo[3.1.1]heptanyl, Octahydro-4,7-methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch -(C-|-C4)-Alkyl, -C(O)-O-RI 3 oder Phenyl substituiert ist, oder 5) -(Crj-C4)-Alkylen-Indolyl, stehen, R13 für 1) Wasserstoffatom,4) - (Co-C4) -alkylene- (C3-C <| 2J-CyC 1 Oa 1 W. where cycloalkyl is selected from the group consisting cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantane tanyl, 1, 7,7- Trimethyl-bicyclo [3.1.1] heptanyl, octahydro-4,7-methano-indenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently of one another once, twice, three or four times by - (C- | C4) alkyl, -C (O) -O-RI3 or phenyl, or 5) - (Crj-C4) -alkylene-indolyl, R 13 is 1) hydrogen,
2) -(C1-C4)^IkYl,2) - (C 1 -C 4 ) ^ IkYl,
3) -(Co-C4)-Alkylen-C(O)-O-R14,3) - (Co-C4) -alkylene-C (O) -O-R14,
4) -(C0-C4)-Alkylen-C(O)-R14 oder 5) -(Crj-C4)-Aikylen-O-R14 steht,4) - (C 0 -C 4 ) -alkylene-C (O) -R 14 or 5) - (Crj-C 4 ) -alkylene-O-R 14,
R14 für Wasserstoff atom, -(Ci-C4)-Alkyl, -NH2 oder -OH steht undR 14 is hydrogen, - (C 1 -C 4 ) -alkyl, -NH 2 or -OH and
R15 für Wasserstoffatom, -(Ci-C4)-Alkyl, -0-CF3, -NH2, -OH, -CF3 oder Halogen steht.R 15 is hydrogen, - (C 1 -C 4 ) -alkyl, -O-CF 3 , -NH 2 , -OH, -CF 3 or halogen.
Die Erfindung betrifft auch die Verwendung der Verbindung der Formel I, wobei X für -SO2- steht,The invention also relates to the use of the compound of formula I wherein X is -SO 2 -,
R1 für 1) Wasserstoffatom oderR1 for 1) hydrogen atom or
2) -(Ci-C4)-Alkyl, steht,2) - (C 1 -C 4 ) -alkyl,
R2 für 1) -(C1-C6)-Alkylen-NH2, 2) -(C0-C4)-Alkylen-Pyridyl-NH2,R 2 for 1) - (C 1 -C 6 ) -alkylene-NH 2 , 2) - (C 0 -C 4 ) -alkylene-pyridyl-NH 2 ,
3) -(Cfj-C4)-Alkylen-Piperidinyl-NH2,3) - (Cfj-C 4 ) -alkylene-piperidinyl-NH 2,
4) -(Cn-C4)-Alkylen-Thiazolyl-NH2,4) - (Cn-C 4 ) -alkylene-thiazolyl-NH 2 ,
5) -(C1-C6)-Alkylen-NH-C(=NH)-NH2,5) - (C 1 -C 6 ) -alkylene-NH-C (= NH) -NH 2 ,
6) -(Co-C4)-Alkylen-(C3-C8)-Cycloalkyl-NH2, 7) -(C1-C6)-Alkylen-NH-C(=NH)-(C1-C4)-Alkyl,6) - (Co-C 4 ) -alkylene- (C 3 -C 8) -cycloalkyl-NH 2, 7) - (C 1 -C 6) -alkylene-NH-C (= NH) - (C 1 -C 4 ) - alkyl,
8) -(C0-C4)-Alkylen-O-NH-C(=NH)-NH2,8) - (C 0 -C 4 ) -alkylene-O-NH-C (= NH) -NH 2 ,
9) -(C1 -C6)-Alkylen-N H-C(O)-O-(C -i -C4)-Alkylen-Aryl, wobei Aryl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist, 10) -(C0-C4)-Alkylen-NH-C(O)-(C1-C4)-Alkyl,9) - (C 1 -C 6) -alkylene-N HC (O) -O- (C 1 -C 4 ) -alkylene-aryl, wherein aryl is unsubstituted or substituted by -NH 2 or by -NH 2 and in, is substituted twice or three times by R 15, 10) - (C 0 -C 4 ) -alkylene-NH-C (O) - (C 1 -C 4 ) -alkyl,
11) -(Co-C4)-Alkylen-(C6-C-|4)-Aryl, wobei Aryl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist, oder 12) -(Ci-C4)-Alkylen-SOχ-(Ci-C4)-Alkylen-NH2 , worin x die ganze Zahl Null,11) - (Co-C4) alkylene- (C6-C- | 4) -aryl, wherein aryl is unsubstituted or substituted by -NH 2 or -NH 2 and mono-, di- or trisubstituted by R15, or 12) - (C 1 -C 4) -alkylene-SOχ- (C 1 -C 4) -alkylene-NH 2, where x is the integer zero,
1 oder 2 bedeutet, steht, R3 für 1) -(C-|-C4)-Alkyl,1 or 2, R 3 is 1) - (C 1 -C 4 ) -alkyl,
2) -(C0-C4)-Alkylen-(C3-C8)-Cycloalkyl, 3) -(C-|-C6)-Alkylen-Aryl, wobei Aryl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,2) - (C 0 -C 4) -alkylene- (C 3 -C 8) -cycloalkyl, 3) - (C 1 -C 6) -alkylene-aryl, where aryl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15 .
4) -(C1-C6)-Alkylen-NH-C(O)-O-(C1-C4)-Alkylen-Aryl, wobei Aryl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,4) - (C 1 -C 6 ) -alkylene-NH-C (O) -O- (C 1 -C 4) -alkylene-aryl, where aryl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15,
5) -(C-i-C^-Alkylen-NH-PG, 6) -(C-i-C6)-Alkylen-O-PG,5) - (C 1 -C 4 -alkylene-NH-PG, 6) - (C 1 -C 6 ) -alkylene-O-PG,
7) -(Ci-C6)-Alkyl, oder7) - (Ci-C6) alkyl, or
8) Wasserstoffatom, steht, wobei PG für t-Butyl-, t-Butyloxycarbonyl oder Benzyloxycarbonyl steht, R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander für8) hydrogen, wherein PG is t-butyl, t-butyloxycarbonyl or benzyloxycarbonyl, R4 is -N (R6) 2, wherein R6 are the same or different and independently of one another
1) Wasserstoffatom,1) hydrogen atom,
2) -(C^C^-Alkyl,2) - (C 1 -C 4) -alkyl,
3) -(Co-C4)-Alkylen-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R11, Halogen, -C(O)-O-RH , -(C<|-C4)-Alkyl-O-R11 oder -O-(C<|-C4)-Alkyl substituiert ist,3) - (Co-C4) -alkylene- (C3-C12) -cycloalkyl, where cycloalkyl is unsubstituted or independently of one another once, twice, three or four times by R11, halogen, -C (O) -O-RH, (C 1-C 4) -alkyl-O-R 11 or -O- (C 1-C4) -alkyl,
4) -(C0-C4)-Alkylen-C(R11 )(R12)-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-RH , -(C-i^-Alkyl-O-RH oder -0-(C1 -C4)-Alkyl substituiert ist,4) - (C 0 -C 4 ) -alkylene-C (R 11) (R 12) - (C 3 -C 12) -cycloalkyl, where cycloalkyl is unsubstituted or independently mono-, di- or trisubstituted by R 11, halogen, -C (O) -O-RH, - (C 1-4) alkyl-O-RH or -O- (C 1 -C 4 ) -alkyl,
5) -(Co-C4)-Alkylen-Het, wobei unter Het ein 4- bis 15-gliedriges heterocyclisches Ringsystem verstanden wird mit 4 bis 15 Ringatomen, die in ein, zwei oder drei miteinander verbundenen Ringsystemen vorliegen und die ein, zwei, drei oder vier gleiche oder verschiedene Heteroatome aus der Reihe Sauerstoff, Stickstoff oder Schwefel enthalten, wobei Het oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-RH , -(C-|-C4)-Alkyl-O-R11 oder -O-(Ci-C4)-Alkyl substituiert sind,5) - (Co-C4) -alkylene-Het, where Het is a 4- to 15-membered heterocyclic ring system is understood with 4 to 15 ring atoms, which are present in one, two or three interconnected ring systems and the one, two, contain three or four identical or different heteroatoms from the series oxygen, nitrogen or sulfur, wherein Het or alkylene unsubstituted or independently of one another once, twice or three times by R 11, halogen, -C (O) -O-RH, - (C 1 -C 4 ) -alkyl-O-R 11 or -O- (Ci-C 4 ) Alkyl are substituted,
6) -(Crj-CßJ-Alkylen-Aryl, wobei Aryl oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11, Halogen,6) - (Crj-CβJ-alkylene-aryl, wherein aryl or alkylene is unsubstituted or independently of one another mono-, di- or trisubstituted by R11, halogen,
-C(O)-O-R11 , -(Crj-C4)-Alkyl-O-R11 oder -O-(Ci-C4)-Alkyl substituiert sind,-C (O) -O-R11, - (Crj-C 4) are substituted alkyl-O-R11 or -O- (Ci-C4) alkyl,
7) -(Cn-C4)-Alkylen-C(R11)(R12)-Aryl, wobei Aryl oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-RH , -(C0-C4)-Alkyl-O-R11 oder -0-(C1 -C4)-Alkyl substituiert sind,7) - (Cn-C4) -alkylene-C (R11) (R12) -aryl, wherein aryl or alkylene is unsubstituted or independently mono-, di- or trisubstituted by R11, halogen, -C (O) -O-RH , - (C 0 -C 4 ) -alkyl-O-R 11 or -O- (C 1 -C 4 ) -alkyl,
8) 1 ,2,3,4-Tetrahydro-naphthalenyl,8) 1, 2,3,4-tetrahydro-naphthalenyl,
9) -(C0-C4)-Alkylen-CH(R11 )-C(O)-NH2,9) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH 2,
10) -(C0-C4)-Alkylen-CH(R11)-C(O)-NH-(C1-C4)-Alkyl,10) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH- (C 1 -C 4 ) -alkyl,
11 ) -(C0-C4)-Alkylen-CH(R 11 )-C(O)-NH-CH(R 12)-R 13, 12) -(Crj-C6)-Alkylen-C(O)-O-R11 , wobei Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch R11 , Halogen, -C(O)-O-R11 , -(C-|-C4)-Alkyl-O-R11 oder -O-(C-|-C4)-Alkyl substituiert ist,11) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH-CH (R 12) -R 13, 12) - (Cr j -C 6) -alkylene-C (O ) -O-R11, in which alkyls are unsubstituted or independently of one another once or twice by R 11, halogen, -C (O) -O-R 11, - (C 1 -C 4 ) -alkyl-O-R 11 or -O- (C 1 -C 4 ) -alkyl is substituted,
13) -(C0-C4)-Alkylen-C(R11 )(R12)-C(O)-O-R11 , oder13) - (C 0 -C 4 ) -alkylene-C (R 11) (R 12) -C (O) -O-R 11, or
14) -(C<|-C3)-Fluoralkyl, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom, an das sie gebunden sind, einen mono- oder bicyclischen Ring mit 4 bis 9 Ringatomen bilden, der gesättigt, teilweise gesättigt oder aromatisch ist, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(Ci-C4)-Alkyl, -C(O)-O-R11 ,14) - (C <| - C3) fluoroalkyl, or the two radicals R6 together with the N atom to which they are attached form a mono- or bicyclic ring having 4 to 9 ring atoms, which is saturated, in part is saturated or aromatic, the ring being unsubstituted or mono- or disubstituted by - (C 1 -C 4 ) -alkyl, -C (O) -O-R 11,
Halogen, -(C<|-C4)-Alkyl-O-R11 oder Phenyl substituiert ist, R7 für Wasserstoffatom oder -(C 1 -C4)-Alkyl steht, R9 für Wasserstoffatom oder -(C-|-C4)-Alkyl steht,Halogen, - (C <| - C 4 ) -alkyl-O-R11 or phenyl, R7 is hydrogen or - (C 1 -C 4 ) -alkyl, R 9 is hydrogen or - (C- | -C 4 ) -Alkyl,
R11 und R12 gleich oder verschieden sind und unabhängig voneinander fürR11 and R12 are the same or different and independently of each other
1) Wasserstoffatom,1) hydrogen atom,
2) -(C1-C4)-Alkyl, 3) -(Co-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch Halogen, -OH oder -O-(C-|-C4)-Alkyl substituiert ist,2) - (C 1 -C 4 ) -alkyl, 3) - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or independently of one another mono-, di- or trisubstituted by halogen, -OH or -O- (C 1 -C 4) -alkyl,
4) -(Cn-C4)-Alkylen-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R13,4) - (C 1 -C 4) -alkylene- (C 3 -C 12) -cycloalkyl, where cycloalkyl is unsubstituted or independently of one another once, twice, three or four times by R 13,
Halogen, -C(O)-O-RI 3, -(C-i^-Alkyl-O-RIS, -O-(Ci-C4)-Alkyl oder -(Co-C4)-Alkylen-Phenyl substituiert ist,Halogen, -C (O) -O-RI 3, - (C 1 -C 4 ) alkyl-O-RIS, -O- (C 1 -C 4 ) -alkyl or - (C 1 -C 4 ) -alkylene-phenyl,
5) -(Cn-C4)-Alkylen-C(O)-N(R13)2 oder5) - (Cn-C4) -alkylene-C (O) -N (R13) 2 or
6) -(Cn-C4)-Alkylen-Indolyl, stehen, R13 für 1) Wasserstoffatom,6) - (C 1 -C 4) -alkylene-indolyl, R 13 is 1) hydrogen,
2) -(C-i-C^-Alkyl,2) - (C 1 -C 4) -alkyl,
3) -(Co-C4)-Alkylen-C(O)-O-R14,3) - (Co-C 4 ) -alkylene-C (O) -O-R 14,
4) -(Cn-C4)-Alkylen-C(O)-R14 oder4) - (Cn-C4) -alkylene-C (O) -R14 or
5) -(Co-C4)-Alkylen-O-R14 steht, R14 für Wasserstoffatom, -(C-|-C4)-Alkyl, -NH2 oder -OH, steht und5) - (Co-C4) -alkylene-O-R14, R14 represents hydrogen, - (C- | -C4) -alkyl, -NH2 or -OH, and
R15 für Wasserstoff atom, -(C-|-C4)-Alkyl, -0-CF3, -NH2, -OH, -CF3 oder Halogen steht.R 15 is hydrogen atom, - (C 1 -C 4 ) -alkyl, -O-CF 3 , -NH 2 , -OH, -CF 3 or halogen.
Die Erfindung betrifft auch die Verwendung der Verbindung der Formel I, wobei X für -SO2- steht,The invention also relates to the use of the compound of formula I wherein X is -SO 2 -,
R1 für 1) Wasserstoffatom oder 2) -(Ci-C4)-Alkyl, steht,R 1 represents 1) hydrogen or 2) - (C 1 -C 4 ) -alkyl,
R2 für 1) -(Ci-C6)-Alkylen-NH2,R 2 for 1) - (C 1 -C 6) -alkylene-NH 2 ,
2) -(Ci-C4)-Alkylen-Pyridyl-NH2) 3) -(C-i-C4)-Alkylen-Piperidinyl-NH2,2) - (C 1 -C 4) -alkylene-pyridyl-NH 2) 3) - (C 1 -C 4) -alkylene-piperidinyl-NH 2 ,
4) -(C-|-C6)-Alkylen-NH-C(=NH)-NH2,4) - (C 1 -C 6) -alkylene-NH-C (= NH) -NH 2,
5) -(Cn-C4)-Alkylen-(C3-C6)-Cycloalkyl-NH2,5) - (Cn-C4) -alkylene- (C3-C6) -cycloalkyl-NH2,
6) -(Ci-C6)-Alkylen-NH-C(=NH)-(C1-C4)-Alkyl,6) - (Ci-C6) alkylene-NH-C (= NH) - (C 1 -C 4) -alkyl,
7) -(Ci-C4)-Alkylen-O-NH-C(=NH)-NH2i 8) -(Ci-C6)-Alkylen-NH-C(O)-O-(C-|-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist,7) - (C 1 -C 4 ) -alkylene-O-NH-C (= NH) -NH 2i 8) - (C 1 -C 6) -alkylene-NH-C (O) -O- (C 1 -C 4) -alkylene-phenyl, wherein phenyl is unsubstituted or substituted by -NH 2 or by -NH 2 and one, two or is substituted by R15 in triplicate,
9) -(C <| -C4)-Alkylen-N H-C(O)-(C -| -C6)-Alkyl, 10) -(C-j-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist,9) - (C 1 -C 4 ) -alkylene-N HC (O) - (C 1 -C 6 ) -alkyl, 10) - (C 1 -C 4 ) -alkylene-phenyl, where phenyl is unsubstituted or substituted by NH2 is substituted by -NH2 and mono-, di- or trisubstituted by R15,
11) -(C1-C4)-Alkylen-SO2-(C1-C4)-Alkylen-NH2, oder11) - (C 1 -C 4) -alkylene-SO2- (C1-C4) alkylene-NH2, or
12) -(C-|-C4)-Alkylen-S-(Ci-C4)-Alkylen-NH2, steht, R3 für 1) -(C-i-C4)-Alkyl,12) - (C- | -C4) alkylene-S- (CiC 4) alkylene-NH 2, R 3 represents 1) - (CiC 4) -alkyl,
2) -(C1-C4)-Alkylen-(C3-C6)-Cycloalkyl,2) - (C 1 -C 4 ) -alkylene- (C 3 -C 6) -cycloalkyl,
3) -(C-|-C4)-Alkyien-Phenyl, wobei Phenyl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,3) - (C 1 -C 4) -alkyl-phenyl, where phenyl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15,
4) -(Ci-C6)-Alkylen-NH-C(O)-O-(C-|-C4)-Alkylen-Phenyl, wobei Phenyl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,4) - (C 1 -C 6) -alkylene-NH-C (O) -O- (C 1 -C 4) -alkylene-phenyl, where phenyl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15,
5) Wasserstoffatom steht, R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander für 1) Wasserstoff atom, 2) -(C1-C4)^IkYl,5) is hydrogen, R 4 is -N (R 6) 2, wherein R 6 are the same or different and independently of one another represents 1) hydrogen atom, 2) - (C 1 -C 4 ) 1-IkYl,
3) -(Cn.-C4)-Alkylen-(C3-C<i2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adaman- tanyl, Bicyclo[3.1.1]heptanyl, Decahydro-naphthalenyl, Tetrahydronaph-thalenyl, Octahydro-4,7-methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach substituiert ist durch -(C-|-C4)-Alkyl, -C(O)-O-RH oder3) - (Cn.-C4) alkylene- (C3-C <i2) cycloalkyl, wherein cycloalkyl is selected from the group tanyl cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantane, bicyclo [3.1.1] heptanyl, Decahydro-naphthalenyl, tetrahydronaphthalenyl, octahydro-4,7-methanoindenyl or bicyclo [2.2.1] heptanyl and wherein cycloalkyl is unsubstituted or independently substituted once, twice, three or four times by - (C- | -C 4 ) alkyl, -C (O) -O-RH or
-(C-|-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch Halogen substituiert ist,- (C 1 -C 4 ) -alkylene-phenyl, where phenyl is unsubstituted or substituted by halogen,
4) -(Co-C4)-Alkylen-C(R11)(R12)-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adamantanyl, Bicyclo[3.1.1]heptanyl, Decahydro-naphthalenyl, Tetrahydronaphthalenyl, Octahydro-4,7-methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach substituiert ist durch -(C-|-C4)-Alkyl, -C(O)-O-R11 oder -(C<|-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch Halogen substituiert ist,4) - (Co-C 4 ) -alkylene-C (R 11) (R 12) - (C 3 -C 12) -cycloalkyl, where cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, Cyclopropyl, adamantanyl, bicyclo [3.1.1] heptanyl, decahydro-naphthalenyl, tetrahydronaphthalenyl, octahydro-4,7-methanoindenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently of one, two, three or three or quadruply substituted by - (C 1 -C 4) -alkyl, -C (O) -O-R 11 or - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or substituted by halogen,
5) -(Crj-C4)-Alkylen-Het, wobei Het ausgewählt ist aus der Gruppe Acridinyl,5) - (Crj-C4) -alkylene-Het, wherein Het is selected from the group acridinyl,
Azepinyl, Azetidinyl, Aziridinyl, Benzimidazalinyl, Benzimidazolyl, Benzo[1,3]dioxolyl, Benzofuranyl, Benzothiofuranyl, Benzothiophenyl, Benzoxazolyl, Benzthiazolyl, Benztriazolyl, Benztetrazolyl, Benzisoxazolyl,Azepinyl, azetidinyl, aziridinyl, benzimidazalinyl, benzimidazolyl, benzo [1,3] dioxolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,
Benzisothiazolyl, Carbazolyl, 4aH-Carbazolyl, Carbolinyl, Chinazolinyl, Chinolinyl, 4H-Chinolizinyl, Chinoxalinyl, Chinuclidinyl, Chromanyl, Chromenyl, Cinnolinyl, Deca-hydrochinolinyl, Dibenzofuranyl, Dibenzothiophenyl, Dihydrofuran[2,3-b]-tetrahydrofuranyl, Dihydrofuranyl, Dioxolyl, Dioxanyl, 2H, 6H-1 ,5,2-Dithiazinyl, Furanyl, Furazanyl, Imidazolidinyl, Imidazolinyl, Imidazolyl,Benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dibenzofuranyl, dibenzothiophenyl, dihydrofuran [2,3-b] tetrahydrofuranyl, dihydrofuranyl, dioxolyl , Dioxanyl, 2H, 6H-1, 5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
1 H-lndazolyl, Indolinyl, Indolizinyl, Indolyl, 3H-lndolyl, Isobenzofuranyl, Isochromanyl, Isoindazolyl, Isoindolinyl, Isoindolyl, Isochinolinyl (Benzimidazolyl), Isothiazolidinyl, 2-lsothiazoIinyl, Isothiazolyl, Isoxazolyl, Isoxazolidinyl, 2-lsoxazolinyl, Morpholinyl, Naphthyridinyl, Octahydroisochinolinyl, Oxadiazolyl, 1 ,2,3-Oxadiazolyl, 1 ,2,4-Oxadiazolyl, 1 ,2,5-1 H-indazinyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolidinyl, 2-isothiazolinyl, isothiazolyl, isoxazolyl, isoxazolidinyl, 2-isoxazolinyl, morpholinyl, naphthyridinyl, Octahydroisoquinolinyl, oxadiazolyl, 1, 2,3-oxadiazolyl, 1, 2,4-oxadiazolyl, 1, 2,5-
Oxadiazolyl, 1 ,3,4-Oxadiazolyl, Oxazolidinyl, Oxazolyl, Oxazolidinyl, Oxothiolanyl, Pyrimidinyl, Phenanthridinyl, Phenanthrolinyl, Phenazinyl, Phenothiazinyl, Phenoxathiinyl, Phenoxazinyl, Phthalazinyl, Piperazinyl, Piperidinyl, Pteridinyl, Purynyl, Pyranyl, Pyrazinyl, Pyroazolidinyl, Pyrazolinyl, Pyrazolyl, Pyridazinyl, Pryidooxazolyl, Pyridoimidazolyl, Pyridothiazolyl,Oxadiazolyl, 1, 3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, oxothiolanyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, Pyrazolyl, pyridazinyl, pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl,
Pyridothiophenyl, Pyridinyl, Pyridyl, Pyrimidinyl, Pyrrolidinyl, Pyrrolinyl, 2H- Pyrrolyl, Pyrrolyl, Tetrahydrofuranyl, Tetrahydroisochinolinyl, Tetrahydrochinolinyl, Tetra hydropyridinyl, 6H-1 ,2,5-Thiadazinyl, 1 ,2,3- Thiadiazolyl, 1 ,2,4-Thiadiazolyl, 1 ,2,5-Thiadiazolyl, 1 ,3,4-Thiadiazolyl, Thianthrenyl, Thiazolyl, Thienyl, Thienoimidazolyl, Thienooxazolyl,Pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl, 6H-1, 2,5-thiadazinyl, 1, 2,3-thiadiazolyl, 1, 2,4 Thiadiazolyl, 1, 2,5-thiadiazolyl, 1, 3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienoimidazolyl, thienooxazolyl,
Thienopyridin, Thienothiazolyl, Thiomorpholinyl, Thiophenyl, Triazinyl, 1 ,2,3- Triazolyl, 1 ,2,3-Triazolyl, 1 ,2,4-Triazolyl, 1 ,2,5-Triazolyl, 1 ,3,4-Triazolyl und Xanthenyl, wobei Het oder Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch -(Ci-C4)-Alkyl substituiert istThienopyridine, thienothiazolyl, thiomorpholinyl, thiophenyl, triazinyl, 1, 2,3-triazolyl, 1, 2,3-triazolyl, 1, 2,4-triazolyl, 1, 2,5-triazolyl, 1, 3,4-triazolyl and Xanthenyl, wherein Het or alkylene is unsubstituted or independently of one another mono- or disubstituted by - (Ci-C 4 ) alkyl substituted
6) -(C-j-C6)-Alkylen-Phenyl, wobei Phenyl oder Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Halogen, Phenyl, -C(O)-O-R11 , -(Ci-C4)-A!ky!-O-R11 , -O^C-i-C^-Alkyl oder -(C-|-C4)-Alkyl substituiert sind,6) - (Cj-C6) -alkylene-phenyl, wherein phenyl or alkylene unsubstituted or independently of one another by one or two halo by halogen, phenyl, -C (O) -O-R11, - (Ci-C 4 ) -A! ky! -O-R11, -O ^ CiC ^ -alkyl or - (C- | -C 4 ) -alkyl are substituted,
7) -(Co-C4)-Alkylen-C(R11 )(R12)-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch Phenyl oder Fluor substituiert ist, 8) 1 ,2,3,4-Tetrahydro-naphthalenyl,7) - (Co-C4) -alkylene-C (R11) (R12) -phenyl, wherein phenyl is unsubstituted or independently mono-, di- or trisubstituted by phenyl or fluorine, 8) 1, 2,3,4 tetrahydro-naphthalenyl,
9) -(C0-C4)-Alkylen-CH(R11 )-C(O)-NH2,9) - (C 0 -C 4) alkylene-CH (R11) -C (O) -NH 2,
10) -(Cn-C4)-Alkylen-CH(R11)-C(O)-N H-(C -|-C4)-Alkyl,10) - (C 1 -C 4 ) -alkylene-CH (R 11) -C (O) -N H- (C 1 -C 4 ) -alkyl,
11 ) -(C0-C4)-Alkylen-CH(R11 )-C(O)-NH-CH(R12)-R13,11) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH-CH (R 12) -R 13,
12) -(C-|-C6)-Alkylen-C(O)-O-R11 , wobei Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Halogen, Phenyl,12) - (C 1 -C 6) -alkylene-C (O) -O-R 11, where alkylene is unsubstituted or independently of one another by halogen, phenyl,
-C(O)-O-RH , -(C<|-C4)-Alkyl-O-R11 , -O-(C-|-C4)-Alkyl oder -(C-|-C4)-Alkyl substituiert ist,-C (O) -O-RH, - (C 1 -C 4 ) -alkyl-O-R 11, -O- (C 1 -C 4 ) -alkyl or - (C 1 -C 4 ) - Alkyl is substituted,
13) -(C0-C4)-Alkylen-C(R11 )(R12)-C(O)-O-R11 , oder13) - (C 0 -C 4 ) -alkylene-C (R 11) (R 12) -C (O) -O-R 11, or
14) -(Ci-C3)-Fluoralkyl, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom an das sie gebunden sind einen Mono- oder Bicyclischen Ring bilden ausgewählt aus der Gruppe Pyrrolidin, Piperidin, 2-Aza-bicyclo[3.2.2]nonan und 7-Aza-bicyclo[2.2.1]hep-tan, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(C-|-C4)-Alkyl, -14) - (Ci-C3) -Fluoralkyl, or the two radicals R6 together with the N-atom to which they are attached form a mono- or bicyclic ring selected from the group pyrrolidine, piperidine, 2-azabicyclo [ 3.2.2] nonane and 7-azabicyclo [2.2.1] hep-tane, where the ring is unsubstituted or mono- or disubstituted by - (C 1 -C 4 ) -alkyl,
C(O)-O-R11 , -(Ci-C4)-Alkyl-O-R11 oder Phenyl substituiert ist, R7 für Wasserstoffatom oder -(C 1 -C4)-Alkyl steht, R9 für Wasserstoffatom oder -(Ci-C4)-Alkyl steht,C (O) -O-R11, - (Ci-C4) -alkyl-O-R11 or phenyl, R7 is hydrogen atom or - (C 1 -C 4) alkyl, R9 is hydrogen atom or - (C -C 4 ) -alkyl,
R11 und R12 gleich oder verschieden sind und unabhängig voneinander fürR11 and R12 are the same or different and independently of each other
1) Wasserstoffatom,1) hydrogen atom,
2) -(C1-C4J-AIRyI, 3) -(Co-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch -OH, Halogen oder -O-(C-j-C4)-Alkyl substituiert ist,2) - (C 1 -C 4 ) -alkyl, 3) - (Co-C4) -alkylene-phenyl, where phenyl is unsubstituted or independently of one another mono-, di- or trisubstituted by -OH, halogen or -O- (Cj-C4) -alkyl,
4) -(Co-C4)-A!kylen-(C3-C-|2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adamantanyl,4) - (Co-C4) -alkylene- (C3-C- | 2) -cycloalkyl, where cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl,
Bicyclo[3.1.1]heptanyl, Octahydro-4,7-methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch -(C-j-C^-Alkyl,Bicyclo [3.1.1] heptanyl, octahydro-4,7-methanoindenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently mono-, di-, tri- or tetra-substituted by - (C 1 -C 4) -alkyl,
-C(O)-O-RI 3 oder Phenyl substituiert ist, oder 5) -(Crj-C4)-Alkylen-Indolyl, stehen,-C (O) -O-RI 3 or phenyl, or 5) - (Crj-C4) -alkylene-indolyl,
R13 für 1 ) Wasserstoff atom,R13 for 1) hydrogen atom,
2) -(C1-C4J-AIlCyI.2) - (C 1 -C 4 J-AIl C y I.
3) -(C0-C4)-Alkylen-C(O)-O-R14,3) - (C 0 -C 4 ) -alkylene-C (O) -O-R 14,
4) -(C0-C4)-Alkylen-C(O)-R14 oder 5) -(C0-C4)-Alkylen-O-R14 steht, und4) - (C 0 -C 4 ) -alkylene-C (O) -R 14 or 5) - (C 0 -C 4) -alkylene-O-R 14, and
R14 für Wasserstoffatom, -(C-|-C4)-Alkyl, -NH2 oder -OH steht und R15 für Wasserstoffatom, -(C1-C4)-Alkyl, -0-CF3, -NH2, -OH, -CF3 oder Halogen steht.R 14 is hydrogen, - (C 1 -C 4 ) -alkyl, -NH 2 or -OH and R 15 is hydrogen, - (C 1 -C 4 ) -alkyl, -O-CF 3 , -NH 2 , -OH, -CF 3 or halogen.
Die Erfindung betrifft auch die Verwendung der Verbindung der Formel I, wobei X für -SO2- steht, R1 für 1) Wasserstoffatom oderThe invention also relates to the use of the compound of the formula I, wherein X is -SO 2 -, R 1 is 1) hydrogen or
2) -(C<|-C4)-Alkyl, steht,2) - (C <| -C4) alkyl, is,
R2 für 1) -(Ci-C6)-Alkylen-NH2, 2) -(Ci-C4)-Alkylen-Pyridyl-NH2,R 2 for 1) - (C 1 -C 6) -alkylene-NH 2, 2) - (C 1 -C 4) -alkylene-pyridyl-NH 2,
3) -(Ci-C4)-Alkylen-Piperidinyl-NH2,3) - (C 1 -C 4) -alkylene-piperidinyl-NH 2,
4) -(C1-C4)-Alkylen-NH-C(=NH)-NH2,4) - (C 1 -C 4) alkylene-NH-C (= NH) -NH 2,
5) -(C-|-C6)-Alkylen-NH-C(=NH)-(C1-C4)-Alkyl,5) - (C 1 -C 6 ) -alkylene-NH-C (= NH) - (C 1 -C 4 ) -alkyl,
6) -(Ci-C4)-Alkylen-(C3-C6)-Cycloalkyl-NH2, 7) -(Ci-C4)-Alkylen-O-NH-C(=NH)-NH2j 6) - (C 1 -C 4 ) -alkylene- (C 3 -C 6 ) -cycloalkyl-NH 2 , 7) - (C 1 -C 4) -alkylene-O-NH-C (= NH) -NH 2j
8) -(C1-C6)-Alkylen-NH-C(O)-O-(C1-C4)-Alkylen-Phenyl,8) - (C 1 -C 6 ) -alkylene-NH-C (O) -O- (C 1 -C 4 ) -alkylene-phenyl,
9) -(C1-C4)-Alky!en-NH-C(O)-(Ci-C6)-Alkyl oder9) - (C 1 -C 4 ) -alkyl-NH-C (O) - (C 1 -C 6 ) -alkyl or
10) -(C1-C4)-Alkylen-Phenyl-NH2, 11) -(Ci-C2)-Alky!en-SO2-(Ci-C4)-Alkylen-NH2, oder10) - (C 1 -C 4 ) -alkylene-phenyl-NH 2 , 11) - (C 1 -C 2 ) -alkyl-SO 2 - (C 1 -C 4 ) -alkylene-NH 2 , or
12) -(Ci-C2)-Alkylen-S-(C1-C4)-Alkylen-NH2, steht,12) - (C 1 -C 2 ) -alkylene-S- (C 1 -C 4) -alkylene-NH 2 ,
R3 für 1) -(Ci-C4)-Alkyl,R 3 is 1) - (C 1 -C 4) -alkyl,
2) -(Ci-C4)-Alkyten-(C3-C6)-Cycloalkyl,2) - (C 1 -C 4) -alkyl (C 3 -C 6) -cycloalkyl,
3) -(C-i-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch -OH substituiert ist,3) - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or substituted by -OH,
4) -(C -i -C6)-Alkylen-NH-C(O)-O-(C «j -C4)-Alkylen-Phenyl,4) - (C -i -C6) alkylene-NH-C (O) -O- (C "j-C4) alkylene-phenyl,
5) Wasserstoffatom steht, R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander für 1) Wasserstoffatom,5) hydrogen, R4 is -N (R6) 2, where R6 are identical or different and independently of one another represent 1) hydrogen atom,
2) -(C1-C6JnAIlCyI,2) - (C 1 -C 6 -alkynyl,
3) -(Co-C4)-Alkylen-(C3-C8)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclopropyl, Adamantanyl, 1 ,7,7- Trimethyl-bicyclo[3.1.1]heptanyl, Decahydro-naphthalenyl, Octahydro-4,7- methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch -(C-|-C4)-Alkyl oder Phenyl substituiert ist,3) - (C 1 -C 4) -alkylene- (C 3 -C 8) -cycloalkyl, where cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclopropyl, adamantanyl, 1, 7,7-trimethyl-bicyclo [3.1.1] heptanyl, Decahydro-naphthalenyl, octahydro-4,7-methano-indenyl or bicyclo [2.2.1] heptanyl and wherein cycloalkyl is unsubstituted or independently mono-, di- or trisubstituted by - (C 1 -C 4) -alkyl or phenyl .
4) -C(R11)(R12)-Adamantanyl,4) -C (R11) (R12) adamantanyl,
5) -CH(RI 1)-C(O)-NH-CH(R12)-R13, 6) -(Crj-C4)-Alkylen-Het, wobei Het ausgewählt ist aus der Gruppe5) -CH (RI 1) -C (O) -NH-CH (R 12) -R 13, 6) - (Cr 1 -C 4) -alkylene-Het, wherein Het is selected from the group
Benzimidazolyl, Isoxazolyl, Piperidinyl, Pyridyl, Pyrrolidinyl, Thiophenyl und Benzo[1 ,3]dioxolyl, 7) 1 ,2,3,4-Tetrahydro-naphthalenyl, 8) -(Co-C4)-Alkylen-C(R11 )(R12)-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch Phenyl oder Fluor substituiert ist,Benzimidazolyl, isoxazolyl, piperidinyl, pyridyl, pyrrolidinyl, thiophenyl and benzo [1,3] dioxolyl, 7) 1,2,3,4-tetrahydro-naphthalenyl, 8) - (Co-C4) -alkylene-C (R11) (R12) -phenyl, where phenyl is unsubstituted or independently of one another mono-, di- or trisubstituted by phenyl or fluorine,
9) -CH(RH)-C(O)-NH2, 10) -CH(RI 1)-C(O)-NH-CH(R12)-CH2-OH,9) -CH (RH) -C (O) -NH 2 , 10) -CH (RI 1) -C (O) -NH-CH (R 12) -CH 2 -OH,
11) -(C-|-C6)-Alkylen-Phenyl, wobei Phenyl oder Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Chlor, Fluor, -C(O)-O-RH , -(C-|-C4)-Alkyl-O-R11 , -O-(C<|-C4)-Alkyl, Phenyl oder11) - (C 1 -C 6) -alkylene-phenyl, where phenyl or alkylene is unsubstituted or independently of one another by chlorine, fluorine, -C (O) -O-RH, - (C 1 -C 4) -Alkyl-O-R11, -O- (C <| - C 4 ) -alkyl, phenyl or
-(C-|-C4)-Alkyl substituiert sind, 12) -CH(RI I)-C(O)-NH-(C -i-C4)-Alkyl,- (C 1 -C 4 ) -alkyl, 12) -CH (RI 1) -C (O) -NH- (C 1 -C 4 ) -alkyl,
13) -(C0-C4)-Alkylen-C(R11 )(R12)-Bicyclo[3.1.1 ]heptanyl, wobei13) - (C 0 -C 4) -alkylene-C (R 11) (R 12) -bicyclo [3.1.1] heptanyl, wherein
Bicyclo[3.1.1]heptanyl unsubstituiert oder ein- bis vierfach durch -(Ci-C4)-Alkyl substituiert ist,Bicyclo [3.1.1] heptanyl is unsubstituted or substituted one to four times by - (C 1 -C 4) -alkyl,
14) -(C-|-C6)-Alkylen-C(O)-O-R11 , wobei Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Chlor, Fluor,14) - (C 1 -C 6) -alkylene-C (O) -O-R 11, where alkylene is unsubstituted or independently of one another by chlorine, fluorine,
-C(O)-O-RH 1 -(Ci-C4)-Alkyl-O-R11 , -O-(Ci-C4)-Alkyl, Phenyl oder -(C-|-C4)-Alkyl substituiert ist,-C (O) -O-RH 1 - (C 1 -C 4) -alkyl-O-R 11, -O- (C 1 -C 4) -alkyl, phenyl or - (C 1 -C 4) -alkyl,
15) -(C0-C4)-Alkylen-C(R11 )(R12)-C(O)-O-R11 , oder15) - (C 0 -C 4 ) -alkylene-C (R 11) (R 12) -C (O) -O-R 11, or
16) -CH2-CF2-CF3, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom an das sie gebunden sind einen Mono- oder Bicyclischen Ring bilden, ausgewählt aus der Gruppe Pyrrolidine, 2-aza-bicyclo[3.2.2]nonan und 7-aza-bicyclo[2.2.1]heptan, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(Ci-C4)-Alkyl,16) -CH2-CF2-CF3, or the two radicals R6 together with the N-atom to which they are attached form a mono- or bicyclic ring selected from the group consisting of pyrrolidines, 2-aza-bicyclo [3.2.2 ] nonane and 7-aza-bicyclo [2.2.1] heptane, where the ring is unsubstituted or mono- or disubstituted by - (C 1 -C 4) -alkyl,
-C(O)-O-RH , -(Ci-C4)-Alkyl-O-R11 oder Phenyl substituiert ist, R7 für Wasserstoffatom oder -(C 1 -C4)-Alkyl steht, R9 für Wasserstoffatom oder -(C-|-C4)-Alkyl steht,C (O) -O-RH, - (C 1 -C 4) -alkyl-O-R 11 or phenyl, R 7 is hydrogen or - (C 1 -C 4) -alkyl, R 9 is hydrogen or - (C 1 -C 4) -alkyl C 1 -C 4) -alkyl,
R11 und R12 gleich oder verschieden sind und unabhängig voneinander fürR11 and R12 are the same or different and independently of each other
1) Wasserstoffatom,1) hydrogen atom,
2) -(C-i-C^-Alkyl, 3) -(Co-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch -OH, Halogen oder -O-(C-|-C4)-Alkyl substituiert ist,2) - (C 1 -C 4) alkyl, 3) - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or independently of one another mono-, di- or trisubstituted by -OH, halogen or -O- (C 1 -C 4) -alkyl,
4) -(Crj-C4)-Alkylen-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropy!, Adamantanyl,4) - (j Cr C4) -alkylene- (C3-Ci2) -cycloalkyl, wherein cycloalkyl is selected from the group consisting cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl !, adamantanyl,
1 ,7,7-Trimethyl-bicyclo[3.1.1]heptanyl, Octahydro-4,7-methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch -(Ci-C4)-Alkyl, -C(O)-O-RI 3 oder Phenyl substituiert ist, oder 5) -(Crj-C4)-Alkylen-Indolyl, stehen,1, 7,7-trimethyl-bicyclo [3.1.1] heptanyl, octahydro-4,7-methano-indenyl or bicyclo [2.2.1] heptanyl and wherein cycloalkyl unsubstituted or independently of one, two, three or four times is (Ci-C4) alkyl, -C (O) -O-RI 3, or phenyl, or 5) - - by (Cr j-C4) alkylene-indolyl, are provided,
R13 für 1 ) Wasserstoffatom,R 13 is 1) hydrogen,
2) -(C1-C4J-AIkYl,2) - (C 1 -C 4 ) -alkyl,
3) -(Co-C4)-Alkylen-C(O)-O-R14,3) - (Co-C 4) -alkylene-C (O) -O-R14,
4) -(Co-C4)-Alkylen-C(0)-R14 oder 5) -(C0-C4)-Alkylen-O-R14 steht,4) - (Co-C 4 ) -alkylene-C (0) -R 14 or 5) - (C 0 -C 4 ) -alkylene-O-R 14,
R14 für Wasserstoffatom, -(C-|-C4)-Alkyl, -NH2 oder -OH steht und R15 für Wasserstoff atom, -(C-|-C4)-Alkyl, -0-CF3, -NH2, -OH, -CF3 oder Halogen steht.R 14 is hydrogen, - (C 1 -C 4 ) -alkyl, -NH 2 or -OH and R 15 is hydrogen, - (C 1 -C 4 ) -alkyl, -O-CF 3 , -NH 2, -OH , -CF3 or halogen.
Die Erfindung betrifft auch die Verwendung der Verbindung der Formel I, die dadurch gekennzeichnet, dass es sich um eine oder mehrere Erkrankungen aus der Reihe Myokardinfarkt, Angina pectoris und andere Formen des akuten Koronarsyndroms, den Schlaganfall, die peripher vaskulären Erkrankungen, die tiefe Venenthrombose, die Lungenembolie, embolische oder thrombotische Ereignisse bedingt durch kardiale Arrhythmien, kardiovaskuläre Ereignisse wie Restenose nach Revaskularisierung und Angioplastie und ähnlichen Eingriffen wie Stentimplantationen und Bypass- Operationen handelt, oder die Reduktion der Thrombosegefahr nach chirurgischen Eingriffen wie bei Knie- und Hüftgelenksoperationen, oder um die disseminierte intravaskuläre Koagulation, Sepsis und anderen intravaskulären Ereignissen, die mit einer Entzündung einhergehen, Atherosklerose, Diabetes und dem metabolischenThe invention also relates to the use of the compound of the formula I, which is characterized in that it is one or more diseases from the series myocardial infarction, angina pectoris and other forms of acute coronary syndrome, stroke, peripheral vascular diseases, deep vein thrombosis, pulmonary embolism, embolic or thrombotic events due to cardiac arrhythmias, cardiovascular events such as restenosis after revascularization and angioplasty and similar procedures such as stenting and bypass surgery, or the reduction of the risk of thrombosis following surgery such as knee and hip replacement surgery, or the disseminated intravascular coagulation, sepsis and other intravascular events associated with inflammation, atherosclerosis, diabetes and the metabolic
Syndrom und deren Folgen, Tumorwachstum und Tumormetastasierung, entzündliche und degenerative Gelenkserkrankungen wie der rheumatoiden Arthritis und der Arthrose, Störungen des hämostatischen Systems wie Fibrinablagerungen, fibrotische Veränderungen der Lunge wie die chronische obstruktive Lungenerkrankung, das adult respiratory distress Syndrom oder Fibrinablagerungen des Auges nach Augenoperationen oder Verhinderung oder Behandlung von Narbenbildung handelt.Syndrome and its consequences, tumor growth and tumor metastasis, inflammatory and degenerative joint diseases such as rheumatoid arthritis and arthrosis, disorders of the hemostatic system such as fibrin deposits, fibrotic changes in the lung such as chronic obstructive pulmonary disease, adult respiratory distress syndrome or fibrin deposition of the eye following ocular surgery or prevention or treatment of scarring.
Die Erfindung betrifft ferner die Verbindung der Formel IThe invention further relates to the compound of the formula I.
Figure imgf000029_0001
und/oder einer stereoisomeren Form der Verbindung der Formel I und/oder Gemische dieser Formen in jedem Verhältnis, und/oder ein physiologisch verträgliches Salz der
Figure imgf000029_0001
and / or a stereoisomeric form of the compound of formula I and / or mixtures of these forms in any ratio, and / or a physiologically acceptable salt of
Verbindung der Formel I, wobeiA compound of the formula I, wherein
X für -SO2- steht,X is -SO 2 -,
R1 für 1) Wasserstoffatom,R1 for 1) hydrogen atom,
2) -(C1-C6J-AIlCyI, 3) -(Cn-C4)-Alkylen-(C3-C-|2)-Cycloalkyl oder2) - (C 1 -C 6 -alkyl), (3) - (C 1 -C 4 ) -alkylene- (C 3 -C 12) -cycloalkyl or
4) -(C -i -C6)-Alkylen-(Ce-C 14)-Aryl steht,4) - (C 1 -C 6) -alkylene- (Ce-C 14) -aryl,
R2 für den Rest der Formel IlR2 for the rest of Formula II
-(A1)m-A2 (II) steht, worin m die ganze Zahl Null oder 1 bedeutet,- (A1) m -A2 (II), where m is the integer zero or 1,
A1 für 1) -(CH2)rr. worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet,A1 for 1) - (CH2) rr. where n is the integer zero, 1, 2 or 3,
2) -NH-(CH2)n-, worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet,2) -NH- (CH 2) n -, where n is the integer zero, 1, 2 or 3,
3) -NH(Ci -C6)-AlkylHCH2)n-, worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet, 4) -NH((C3-C6)-Cycloalkyl)-(CH2)rr, worin n die ganze Zahl Null, 1 , 2 oder3) -NH (C 1 -C 6 ) -alkylHCH 2 ) n-, where n is the integer zero, 1, 2 or 3, 4) -NH ((C 3 -C 6 ) -cycloalkyl) - (CH 2) rr, where n is the integer zero, 1, 2 or
3 bedeutet,3 means
5) -O-(CH2)n-, worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet, oder 6) -(CH2)n-SOx-, worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet und x die ganze Zahl Null, 1 oder 2 bedeutet, steht, A2 für 1) Het, wobei unter Het ein 4- bis 15-gliedriges heterocyclisches5) -O- (CH 2) n -, wherein n is the integer zero, 1, 2 or 3, or 6) - (CH 2) n-SO x -, wherein n is the integer zero, 1, 2 or 3 and x is the integer zero, 1 or 2, A2 is 1) Het, Het being a 4 - to 15-membered heterocyclic
Ringsystem mit 4 bis 15 Ringatomen verstanden wird, die in ein, zwei oder drei miteinander verbundenen Ringsystemen vorliegen und die ein, zwei, drei oder vier gleiche oder verschiedene Heteroatome aus der Reihe Sauerstoff, Stickstoff oder Schwefel enthalten und unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch ein -(Ci-C3)-Alkyl, Halogen,Ring system comprising 4 to 15 ring atoms which are present in one, two or three interconnected ring systems and which contain one, two, three or four identical or different heteroatoms from the series oxygen, nitrogen or sulfur and are unsubstituted or independently of one another, two or three times by a - (C 1 -C 3) -alkyl, halogen,
-NH2, -CF3 oder -O-CFß substituiert ist, 2) -(Cn-C6)-Alkylen-NH2 ,-NH 2, -CF 3 or -O-CF 8 is substituted, 2) - (C 1 -C 6) -alkylene-NH 2 ,
3) -(C1-C6)-Alkylen-NH-C(=NH)-NH2j 3) - (C 1 -C 6 ) alkylene-NH-C (= NH) -NH 2j
4) -(Ci-C6)-Alkylen-NH-C(=NH)-(C1-C4)-Alkyl,4) - (C 1 -C 6) -alkylene-NH-C (NHNH) - (C 1 -C 4) -alkyl,
5) -(C0-C4)-Alkylen-O-NH-C(=NH)-NH2j 5) - (C 0 -C 4) -alkylene-O-NH-C (= NH) -NH 2j
6) -(C0-C4)-Alkylen-NH-C(O)-(C<|-C6)-Alkyl, 7) -(Ci-C6)-Alkylen-NH-C(O)-O-(Ci-C4)-Alkylen-Aryl, wobei Aryl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist,6) - (C 0 -C 4) -alkylene-NH-C (O) - (C 1 -C 6 ) -alkyl, 7) - (C 1 -C 6 ) -alkylene-NH-C (O) -O- (Ci-C 4) -alkylene-aryl, wherein aryl is unsubstituted or substituted by -NH 2 or -NH 2, and mono-, di- or trisubstituted by R15,
8) -(C3-C8)-Cycloalkyl-NH2, oder8) - (C 3 -C 8) cycloalkyl-NH 2, or
9) -(Co-C4)-Alkylen-(C6-Ci4)-Aryl, wobei Aryl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist, steht, R3 für 1) -(C<|-C6)-Alkyl,9) - (Co-C4) alkylene- (C6-Ci4) aryl, wherein aryl is unsubstituted or substituted by -NH 2 or -NH 2, and mono-, di- or trisubstituted by R15,, R 3 for 1) - (C 1 -C 6) -alkyl,
2) -(C0-C4)-Alkylen-(C3-Ci 2)-Cycloalkyl,2) - (C 0 -C 4) -alkylene- (C 3 -C 2) cycloalkyl,
3) -(Ci-C6)-Alkylen-(C6-C-|4)-Aryl, wobei Aryl unabhängig voneinander ein- , zwei- oder dreifach durch R15 substituiert ist,3) - (C 1 -C 6) -alkylene- (C 6 -C 4) -aryl, where aryl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15,
4) -(Cn-C8)-Alkylen-N(R5)-PG,4) - (Cn-C8) -alkylene-N (R5) -PG,
5) -(C1-C6)-Alkylen-NH-C(O)-O-(C1-C4)-Alkylen-Aryl, wobei Aryl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,5) - (C 1 -C 6) -alkylene-NH-C (O) -O- (C 1 -C 4 ) -alkylene-aryl, where aryl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15,
6) -(Co-C4)-Alkylen-(C6-C14)-Aryl-(Co-C4)-Alkylen-N(R5)-PG, 7) -(Co-C8)-Alkylen-O-PG,6) - (C o -C 4) alkylene- (C 6 -C 14) aryl (Co-C4) -alkylene-N (R5) -PG, 7) - (Co-C8) -alkylene-O-PG,
8) -(Co-C4)-Alkylen-(C6-Ci4)-Aryl-(Co-C4)-Alkylen-O-PG,8) - (Co-C4) -alkylene- (C6-C14) -aryl (Co-C4) -alkylene-O-PG,
9) -(C0-C8)-Alkylen-C(O)-O-PG,9) - (C 0 -C 8 ) -alkylene C (O) -O-PG,
10) -(Co-C4)-Alkylen-(C6-Ci4)-Aryl-(Co-C4)-Alkylen-C(O)-O-PG oder 11) Wasserstoffatom, steht,10) - (Co-C 4 ) -alkylene- (C 6 -C 4) -aryl (Co-C 4 ) -alkylene-C (O) -O-PG or 11) hydrogen,
R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander fürR4 is -N (R6) 2, wherein R6 are the same or different and independently of one another
1 ) Wasserstoffatom ,1) hydrogen atom,
2) -(C1-C6JnAIlCyI1 3) -(Cn-C4)-Alkylen-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R11 , Halogen, -C(O)-O-RH , -(C-|-C4)-Alkyl-O-R11 oder -O-(C-|-C4)-Alkyl substituiert ist,2) - (C 1 -C 6 -alkynyl 1 3) - (C 1 -C 4) -alkylene- (C 3 -C 12) -cycloalkyl, where cycloalkyl is unsubstituted or independently mono-, di-, tri- or tetravalent by R 11, halogen , -C (O) -O-RH, - (C 1 -C 4 ) -alkyl-O-R 11 or -O- (C 1 -C 4 ) -alkyl,
4) -(Co-C5)-Alkylen-(C6-Ci4)-Aryl, wobei Aryl und Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R11 ,4) - (C 0 -C 5) -alkylene- (C 6 -C 14) -aryl, where aryl and alkylene are unsubstituted or independently of one another once, twice, three or four times by R 11,
Halogen, -C(O)-O-RH , -(C1-C4)-Alkyl-O-R11 , -C(O)-N(R8)2 oder -O-(C-|-C4)-Alkyl substituiert sind,Halogen, -C (O) -O-RH, - (C 1 -C 4 ) -alkyl-O-R 11, -C (O) -N (R 8) 2 or -O- (C- | -C 4) - Alkyl are substituted,
5) -(C0-C8)-Alkylen-N(R5)-PG,5) - (C 0 -C 8 ) -alkylene-N (R 5) -PG,
6) -(Co-C4)-Alkylen-(C6-Ci4)-Aryl-(Co-C4)-Alkyl-N(R5)-PG, 7) -(C0-C8)-Alkylen-O-PG,6) - (Co-C 4 ) -alkylene- (C 6 -C 14) -aryl (Co-C 4 ) -alkyl-N (R 5) -PG, 7) - (C 0 -C 8) -alkylene-O-PG .
8) -(Co-C4)-Alkylen-(C6-C14)-Aryl-(Co-C4)-Alkyl-O-PG,8) - (Co-C 4) -alkylene- (C 6 -C 1 4) aryl (Co-C 4) -alkyl-O-PG,
9) -(C0-C8)-Alkylen-C(O)-O-R11 ,9) - (C 0 -C 8) -alkylene-C (O) -O-R 11,
10) -(C0-C4)-Alkylen-(C6-Ci4)-Aryl-(Co-C4)-Alkyl-C(O)-O-PG,10) - (C 0 -C 4 ) -alkylene- (C 6 -C 14) -aryl (Co-C 4 ) -alkyl-C (O) -O-PG,
11) -(Cn-C4)-Alkylen-Het, wobei unter Het ein 4- bis 15-gliedriges heterocyclisches Ringsystem verstanden wird mit 4 bis 15 Ringatomen, die in ein, zwei oder drei miteinander verbundenen Ringsystemen vorliegen und die ein, zwei, drei oder vier gleiche oder verschiedene Heteroatome aus der Reihe Sauerstoff, Stickstoff oder Schwefel enthalten, wobei Het oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-RH , -(Ci-C4)-Alkyl-O-R11 oder -O-(C<|-C4)-Alkyl substituiert sind,11) - (Cn-C4) -alkylene-Het, wherein Het is a 4- to 15-membered heterocyclic ring system is understood with 4 to 15 ring atoms, which are present in one, two or three interconnected ring systems and the one, two, contain three or four identical or different heteroatoms from the series oxygen, nitrogen or sulfur, wherein Het or alkylene unsubstituted or independently of one, two or three times by R 11, halogen, -C (O) -O-RH, - (C 1 -C 4 ) -alkyl-O-R 11 or -O- (C 1 -C 4 ) -alkyl,
12) -(C-j-CaJ-Fluoralkyl,12) - (C-j-CaJ-fluoroalkyl,
13) -(C0-C4)-Alkylen-CH(R11 )-C(O)-NH2, 14) -(C0-C4)-Alkylen-CH(R11)-C(O)-N H-(C 1-C4)-Alkyl,13) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH 2 , 14) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -N H (C 1 -C 4 ) -alkyl,
15) -(C0-C4)-Alkylen-CH(R11 )-C(O)-NH-CH(R12)-R13, oder15) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH-CH (R 12) -R 13, or
16) Aminosäure, wobei die Bindung der Aminosäure über eine Peptid- Bindung erfolgt und der Carboxyl-Rest der Aminosäure unsubstituiert oder durch PG oder durch -N(R5)2 substituiert ist, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom, an das sie gebunden sind, einen mono- oder bicyclischen Ring mit 4 bis 9 Ringatomen bilden, der gesättigt, teilweise gesättigt oder aromatisch ist, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(Ci-C4)-Alkyl, -C(O)-O-R11 ,16) amino acid, wherein the binding of the amino acid takes place via a peptide bond and the carboxyl radical of the amino acid is unsubstituted or substituted by PG or by -N (R5) 2, or the two radicals R6 together with the N-atom to which they are attached form a mono- or bicyclic ring having 4 to 9 ring atoms which is saturated, partially saturated or aromatic, the ring being unsubstituted or mono- or disubstituted by - (C 1 -C 4 ) -alkyl, C (O) -O-R11,
Halogen, -(C-|-C4)-Alkyl-O-R11 oder Phenyl substituiert ist, R5 für Wasserstoffatom oder-(Ci-Ce)-Alkyl steht,Halogen, - (C 1 -C 4 ) -alkyl-O-R 11 or phenyl, R 5 is hydrogen or (C 1 -C 6 ) -alkyl,
PG für eine Schutzgruppe für die Amino-, Carboxyl- oder für die Hydroxyfunktion steht, R7 für Wasserstoffatom oder -(C-i-CßJ-Alkyl steht,PG is a protective group for the amino, carboxyl or for the hydroxyl function, R7 is hydrogen or - (C-i-CβJ-alkyl,
R8 für Wasserstoffatom oder -(C-|-C6)-Alkyl steht, R9 für Wasserstoffatom oder -(C 1 -C6)-Alkyl steht,R 8 is hydrogen or - (C 1 -C 6) -alkyl, R 9 is hydrogen or - (C 1 -C 6) -alkyl,
R11 und R12 gleich oder verschieden sind und unabhängig voneinander fürR11 and R12 are the same or different and independently of each other
1) Wasserstoffatom,1) hydrogen atom,
2) -(C-i-C^-Alkyl,2) - (C 1 -C 4) -alkyl,
3) -(Crj-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch Halogen, -OH oder -0-(C-I-C4)-3) - (Cr j -C 4) -alkylene-phenyl, wherein phenyl is unsubstituted or substituted independently of one another, di- or trisubstituted by halogen, -OH, or -0- (CIC 4) -
Alkyl substituiert ist,Alkyl is substituted,
4) -(Crj-C4)-Alkylen-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R13, Halogen, -C(O)-O-R13, -(C<|-C4)-Alkyl-O-R13, -O-(C-|-C4)-Alkyl oder -(Crj-C4)-Alkylen-Phenyl substituiert ist, 5) -(C0-C4)-Alkylen-C(O)-N(R13)2 oder4) - (Crj-C4) -alkylene- (C3-Ci2) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently mono-, di-, tri- or four times by R13, halogen, -C (O) -O-R13 , - (C <| -C4) alkyl-O-R13, -O- (C- | -C4) alkyl or - (Cr j -C 4) -alkylene-substituted phenyl, 5) - (C 0 -C 4 ) -alkylene-C (O) -N (R 13) 2 or
6) -(Co-C4)-Alkylen-Indolyl, stehen, R13 für 1) Wasserstoffatom,6) - (Co-C4) -alkylene-indolyl, R13 is 1) hydrogen,
2) -(C1-C4J-AIRyI, 3) -(Co-C4)-Alkylen-C(O)-0-R14,2) - (C 1 -C 4 -alkyl-, 3) - (Co-C 4 ) -alkylene-C (O) -O-R 14,
4) -(C0-C4)-Alkylen-C(O)-R14 oder4) - (C 0 -C 4 ) -alkylene-C (O) -R 14 or
5) -(Co-C4)-Alkylen-O-R14 steht,5) - (Co-C 4 ) -alkylene-O-R 14,
R14 für Wasserstoffatom, -(C-|-C4)-Alkyl, -NH2 oder -OH, steht und R15 für Wasserstoffatom, -(C<|-C4)-Alkyl, -O-CF3, -NH2, -OH, -CF3 oder Halogen steht.R14 is hydrogen, - (C- | -C4) alkyl, -NH 2 or -OH, and R15 stands for hydrogen atom, - (C <| -C4) alkyl, -O-CF3, -NH2, - OH, -CF3 or halogen.
Die Erfindung betrifft ferner die Verbindung der Formel I, wobei X für -SO2- steht,The invention further relates to the compound of formula I, wherein X is -SO 2 -,
R1 für 1) Wasserstoffatom oder 2) -(Ci-C4)-Alkyl, steht,R 1 represents 1) hydrogen or 2) - (C 1 -C 4 ) -alkyl,
R2 für 1) -(C1-C6)-Alkylen-NH2> R2 for 1) - (C 1 -C 6 ) -alkylene-NH 2>
2) -(C0-C4)-Alkylen-Pyridyl-NH2,2) - (C 0 -C 4) -alkylene-pyridyl-NH 2,
3) -(Cn-C4)-Alkylen-Piperidinyl-NH2,3) - (Cn-C 4 ) -alkylene-piperidinyl-NH 2 ,
4) -(C0-C4)-Alkylen-Thiazolyl-NH2, 5) -(C-|-C6)-Alkylen-NH-C(=NH)-NH2,4) - (C 0 -C 4 ) -alkylene-thiazolyl-NH 2 , 5) - (C 1 -C 6 ) -alkylene-NH-C (NHNH) -NH 2 ,
6) -(Cn-C4)-Alkylen-(C3-C8)-Cycloalkyl-NH2,6) - (C 1 -C 4 ) -alkylene- (C 3 -C 8) -cycloalkyl-NH 2 ,
7) -(C1-C6)-Alkylen-NH-C(=NH)-(C1-C4)-Alkyl,7) - (C 1 -C 6) -alkylene-NH-C (= NH) - (C 1 -C 4 ) -alkyl,
8) -(Co-C4)-Alkylen-O-NH-C(=NH)-NH2i 8) - (Co-C 4 ) -alkylene-O-NH-C (= NH) -NH 2i
9) -(C1-C6)-Alkylen-NH-C(O)-O-(C1-C4)-Alkylen-Aryl, wobei Aryl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist,9) - (C 1 -C 6) -alkylene-NH-C (O) -O- (C 1 -C 4) -alkylene-aryl, wherein aryl is unsubstituted or substituted by -NH 2 or -NH 2, and is monosubstituted, disubstituted or trisubstituted by R 15,
10) -(Cn-C4)-Alkylen-N H-C(O)-(C 1 -C4)-Alkyl , 11) -(Co-C4)-Alkylen-(C6-C-|4)-Aryl, wobei Aryl unsubstituiert oder durch -IMH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist, oder10) - (Cn-C4) -alkylene-N HC (O) - (C 1 -C 4) -alkyl, 11) - (Co-C4) -alkylene- (C6-C- | 4) -aryl, wherein aryl is unsubstituted or substituted by -IMH2 or substituted by -NH2 and mono-, di- or trisubstituted by R15, or
12) -(Ci-C4)-Alkylen-SOx-(Ci-C4)-Alkylen-NH2 worin x die ganze Zahl Null, 1 oder 2 bedeutet, steht,12) - (C 1 -C 4) -alkylene-SO x - (C 1 -C 4) -alkylene-NH 2 in which x is the integer zero, 1 or 2,
R3 für 1) -(Ci-C4)-Alkyl,R 3 is 1) - (C 1 -C 4) -alkyl,
2) -(C0-C4)-Alkylen-(C3-C8)-Cycloalkyl,2) - (C 0 -C 4) -alkylene- (C 3 -C 8 ) -cycloalkyl,
3) -(Ci-C6)-Alkylen-Aryl, wobei Aryl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist, 4) -(C-|-C6)-Alkylen-NH-C(O)-O-(C-|-C4)-Alkylen-Aryl, wobei Aryl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,3) - (C 1 -C 6) -alkylene-aryl, where aryl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15, 4) - (C 1 -C 6) -alkylene-NH-C (O) -O - (C 1 -C 4) -alkylene-aryl, where aryl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15,
5) -(C<|-C6)-Alkylen-NH-PG,5) - (C <| -C6) alkylene-NH-PG,
6) -(C-|-C6)-Alkylen-O-PG,6) - (C 1 -C 6) -alkylene-O-PG,
7) -(C<|-C6)-Alkyl, oder 8) Wasserstoff atom, steht, wobei PG für t-Butyl-, t-Butyloxycarbonyl oder Benzyloxycarbonyl steht, R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander für7) - (C <| - C6) alkyl, or 8) hydrogen atom, wherein PG is t-butyl, t-butyloxycarbonyl or benzyloxycarbonyl, R4 is -N (R6) 2 , wherein R6 is the same or are different and independent of each other
1 ) Wasserstoffatom , 2) -(C1-Ce)-AIlCyI1 1) hydrogen atom, 2) - (C 1 -Ce) -AIlCyI 1
3) -(Co-C4)-Alkylen-(C3-C-|2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R11 , Halogen, -C(O)-O-RH , -(Ci-C4)-Alkyl-O-R11 oder -0-(C1 -C4)-Alkyl substituiert ist, 4) -(C0-C4)-Alkylen-C(R11 )(R12MC3-C12)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-RH , -(C 1 -C4)-Alkyl-O-R 11 oder -0-(C1 -C4)-Alkyl substituiert ist,3) - (Co-C4) -alkylene- (C3-C- | 2) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently of one another once, twice, three or four times by R11, halogen, -C (O) -O -RH, - (C 1 -C 4 ) -alkyl-O-R 11 or -O- (C 1 -C 4 ) -alkyl, 4) - (C 0 -C 4 ) -alkylene-C (R 11) (R 12 MC 3) C 12) -cycloalkyl, where cycloalkyl is unsubstituted or independently of one another mono-, di- or trisubstituted by R 11, halogen, -C (O) -O-RH, - (C 1 -C 4 ) -alkyl-OR 11 or -O- (C 1 -C 4 ) -alkyl is substituted,
5) -(Crj-C4)-Alkylen-Het, wobei unter Het ein 4- bis 15-gliedriges heterocyclisches Ringsystem verstanden wird mit 4 bis 15 Ringatomen, die in ein, zwei oder drei miteinander verbundenen Ringsystemen vorliegen und die ein, zwei, drei oder vier gleiche oder verschiedene Heteroatome aus der Reihe Sauerstoff, Stickstoff oder Schwefel enthalten, wobei Het oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-RH , -(C-|-C4)-Alkyl-O-R11 oder -O-(C-|-C4)-Alkyl substituiert sind,5) - (Crj-C4) -alkylene-Het, where Het a 4- to 15-membered heterocyclic ring system is understood with 4 to 15 ring atoms, which in are one, two or three interconnected ring systems and contain one, two, three or four identical or different heteroatoms from the series oxygen, nitrogen or sulfur, wherein Het or alkylene is unsubstituted or independently one, two or three times by R11, Halogen, -C (O) -O-RH, - (C 1 -C 4 ) -alkyl-O-R 11 or -O- (C 1 -C 4 ) -alkyl,
6) -(Crj-C6)-Alkylen-Aryl, wobei Aryl oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-RH , -(Cn-C4)-Alkyl-O-R11 oder -O-(C-|-C4)-Alkyl substituiert sind, 7) -(C0-C4)-Alkylen-C(R11)(R12)-Aryl, wobei Aryl oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-RH , -(Crj-C4)-Alkyl-O-R11 oder -O-(Ci-C4)-Alkyl substituiert sind,6) - (Crj-C6) -alkylene-aryl, where aryl or alkylene are unsubstituted or independently of one another mono-, di- or trisubstituted by R11, halogen, -C (O) -O-RH, - (Cn-C4) - Alkyl-O-R11 or -O- (C 1 -C 4 ) -alkyl, 7) - (C 0 -C 4 ) -alkylene-C (R 11) (R 12) -aryl, wherein aryl or alkylene is unsubstituted or independently mono-, di- or trisubstituted by R11, halogen, -C (O) -O-H, - (Crj-C4) -alkyl-O-R11 or -O- (Ci-C4) -alkyl are,
8) 1 ,2,3,4-Tetrahydro-naphthalenyl, 9) -(C0-C4)-Alkylen-CH(R11)-C(O)-NH2,8) 1, 2,3,4-tetrahydro-naphthalenyl, 9) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH 2 ,
10) -(Cn-C4)-Alkylen-CH(R11)-C(O)-NH-(C i-C4)-Alkyl,10) - (C 1 -C 4 ) -alkylene-CH (R 11) -C (O) -NH- (C 1 -C 4 ) -alkyl,
11 ) -(C0-C4)-Alkylen-CH(R11 )-C(O)-NH-CH(R12)-R13,11) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH-CH (R 12) -R 13,
12) -(Crj-C6)-Alkylen-C(O)-O-R11 , wobei Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch R11 , Halogen, -C(O)-O-R11 , -(C-|-C4)-Alkyl-O-R11 oder -O-(C<|-C4)-Alkyl substituiert ist,12) - (Crj-C6) -alkylene-C (O) -O-R11, wherein alkyls are unsubstituted or independently of one another once or twice by R11, halogen, -C (O) -O-R11, - (C- | C 4 ) -alkyl-O-R 11 or -O- (C 1-C 4 ) -alkyl,
13) -(C0-C4)-Alkylen-C(R11 )(R12)-C(O)-O-R11 , oder13) - (C 0 -C 4 ) -alkylene-C (R 11) (R 12) -C (O) -O-R 11, or
14) -(C-|-C3)-Fluoralkyl, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom, an das sie gebunden sind, einen mono- oder bicyclischen Ring mit 4 bis 9 Ringatomen bilden, der gesättigt, teilweise gesättigt oder aromatisch ist, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(Ci-C4)-Alkyl, -C(O)-O-R11 ,14) - (C 1 -C 3) -fluoroalkyl, or the two R 6 together with the N-atom to which they are attached form a mono- or bicyclic ring having 4 to 9 ring atoms, which is saturated, in part is saturated or aromatic, the ring being unsubstituted or mono- or disubstituted by - (C 1 -C 4 ) -alkyl, -C (O) -O-R 11,
Halogen, -(Ci-C4)-Alkyl-O-R11 oder Phenyl substituiert ist, R7 für Wasserstoffatom oder -(C-|-C4)-Alkyl steht, R9 für Wasserstoffatom oder -(C-|-C4)-Alkyl steht, R11 und R12 gleich oder verschieden sind und unabhängig voneinander für 1) Wasserstoffatom,Halogen, (C 1 -C 4 ) -alkyl-O-R 11 or phenyl, R 7 is hydrogen or - (C 1 -C 4 ) -alkyl, R 9 is hydrogen or - (C 1 -C 4 ) -Alkyl, R11 and R12 are the same or different and are each independently 1) hydrogen atom,
2) -(C1-C4MIlCyI,2) - (C 1 -C 4 -methyl)
3) -(Co-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch Halogen, -OH oder -O-(C-|-C4)-Alkyl substituiert ist,3) - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or independently of one another mono-, di- or trisubstituted by halogen, -OH or -O- (C 1 -C 4) -alkyl,
4) -(Co-C4)-Alkylen-(C3-C"i2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R13, Halogen, -C(O)-O-RI 3, -(Ci-C4)-Alkyl-O-R13, -O-(C<|-C4)-Alkyl oder -(Co-C4)-Alkylen-Phenyl substituiert ist, 5) -(Crj-C4)-Alkylen-C(O)-N(R13)2 oder4) - (C 1 -C 4) -alkylene- (C 3 -C 12) -cycloalkyl, where cycloalkyl is unsubstituted or independently of one another once, twice, three or four times by R 13, halogen, -C (O) -O- RI 3, - (Ci-C4) -alkyl-O-R13, -O- (C <| -C4) alkyl or - (Co-C4) alkylene-phenyl, 5) - (CRJ C4) -alkylene-C (O) -N (R13) 2 or
6) -(Cn-C4)-Alkylen-Indolyl, stehen,6) - (Cn-C4) -alkylene-indolyl,
R13 für 1 ) Wasserstoffatom,R 13 is 1) hydrogen,
2) -(C1-C4)-Alkyl,2) - (C 1 -C 4 ) -alkyl,
3) -(C0-C4)-Alkylen-C(O)-O-R14, 4) -(C0-C4)-Alkylen-C(O)-R14 oder3) - (C 0 -C 4 ) -alkylene-C (O) -O-R 14, 4) - (C 0 -C 4 ) -alkylene-C (O) -R 14 or
5) -(Cn-C4)-Alkylen-O-R 14 steht,5) - (Cn-C4) -alkylene-O-R 14,
R14 für Wasserstoffatom, -(C-|-C4)-Alkyl, -NH2 oder -OH, steht und R15 für Wasserstoff atom, -(Ci-C4)-Alkyl, -O-CF3, -NH2, -OH, -CF3 oderR 14 is hydrogen, - (C 1 -C 4) -alkyl, -NH 2 or -OH, and R 15 is hydrogen, - (C 1 -C 4 ) -alkyl, -O-CF 3, -NH 2, -OH, - CF3 or
Halogen steht.Halogen is available.
Die Erfindung betrifft auch die Verwendung der Verbindung der Formel I, wobei X für -SO2- steht, R1 für 1) Wasserstoffatom oder 2) -(C1-C4J-AIkVl, steht, R2 für 1) -(C1-C6)-Alkylen-NH2,The invention also relates to the use of the compound of the formula I in which X is -SO 2 -, R 1 is 1) hydrogen or 2) - (C 1 -C 4 -alkyl), R 2 is 1) - (C 1 - C6) alkylene-NH2,
2) -(C-i-C4)-Alkylen-Pyridyl-NH2,2) - (C 1 -C 4) -alkylene-pyridyl-NH 2,
3) -(C1-C4)-Alkylen-Piperidinyl-NH2,3) - (C 1 -C 4) -alkylene-piperidinyl-NH 2,
4) -(C1-C6)-Alkylen-NH-C(=NH)-NH2,4) - (C 1 -C 6 ) -alkylene-NH-C (= NH) -NH 2 ,
5) -(Co-C4)-Alkylen-(C3-C6)-Cycloalkyl-NH2) 6) -(C1-C6)-Alkylen-NH-C(=NH)-(C1-C4)-Alkyl,5) - (Co-C 4 ) -alkylene- (C 3 -C 6) -cycloalkyl-NH 2) 6) - (C 1 -C 6) -alkylene-NH-C (= NH) - (C 1 -C 4 ) -alkyl,
7) -(C1-C4)-Alkylen-O-NH-C(=NH)-NH2,7) - (C 1 -C 4 ) -alkylene-O-NH-C (= NH) -NH 2,
8) -(C1-C6)-Alkylen-NH-C(O)-O-(C1-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist,8) - (C 1 -C 6) -alkylene-NH-C (O) -O- (C 1 -C 4 ) -alkylene-phenyl, where phenyl is unsubstituted or substituted by -NH 2 or by -NH 2 and is substituted two or three times by R 15,
9) -(C -i -C4)-Alkylen-N H-C(O)-(C 1-C6)-Alkyl,9) - (C 1 -C 4 ) alkylene-N HC (O) - (C 1 -C 6 ) -alkyl,
10) -(C-|-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist, 11) -(Ci-C4)-Alkylen-SO2-(Ci-C4)-Alkylen-NH2, oder10) - (C 1 -C 4 ) -alkylene-phenyl, where phenyl is unsubstituted or substituted by -NH 2 or substituted by -NH 2 and mono-, di- or trisubstituted by R 15, 11) - (C 1 -C 4 ) -Alkylene-SO 2 - (C 1 -C 4 ) -alkylene-NH 2, or
12) -(Ci-C4)-Alkylen-S-(C1-C4)-Alkylen-NH2, steht R3 für 1) -(C-|-C4)-A!kyl,12) - (Ci-C 4) -alkylene-S- (C 1 -C 4) alkylene-NH 2, R 3 is 1) - (C- |! -C 4) alkyl -A,
2) -(C1 -C4)-Alkylen-(C3-C6)-Cycloalkyl,2) - (C 1 -C 4 ) -alkylene- (C 3 -C 6 ) -cycloalkyl,
3) -(C-i-C4)-Alkylen-Phenyl, wobei Phenyl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,3) - (C 1 -C 4 ) -alkylene-phenyl, where phenyl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15,
4) -(Ci-C6)-Alkylen-NH-C(O)-O-(C1-C4)-Alkylen-Phenyl, wobei Phenyl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,4) - (C 1 -C 6 ) -alkylene-NH-C (O) -O- (C 1 -C 4 ) -alkylene-phenyl, where phenyl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15,
5) Wasserstoffatom steht, R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander für5) is hydrogen, R4 is -N (R6) 2, where R6 are the same or different and independently of one another
1) Wasserstoffatom,1) hydrogen atom,
2) -(C1-C4)-Alkyl,2) - (C 1 -C 4 ) -alkyl,
3) -(Crj-C4)-Alkylen-(C3-C<|2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adaman- tanyl, 1 ,7,7-Trimethyl-bicyclo[3.1.1]heptanyl, Decahydro-naphthalenyl,3) - (C 1 -C 4 ) -alkylene- (C 3 -C 12 -cycloalkyl, where cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, 1, 7,7-trimethyl- bicyclo [3.1.1] heptanyl, decahydro-naphthalenyl,
Tetrahydronaphthalenyl, Octahydro-4,7-methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach substituiert ist durch -(C-|-C4)-Alkyl,Tetrahydronaphthalenyl, octahydro-4,7-methano-indenyl or bicyclo [2.2.1] heptanyl and wherein cycloalkyl is unsubstituted or independently substituted mono-, di-, tri- or tetra-substituted by - (C 1 -C 4 ) -alkyl .
-C(O)-O-RH oder -(C-I -C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch Halogen substituiert ist, 4) -(C0-C4)-Alkylen-C(R11)(R12)-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adamantanyl, 1 ,7,7-Trimethy!-bicyclo[3.1.13heptanyl, Decahydro- naphthalen, Tetrahydronaphthalenyl, Octahydro-4,7-methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach substituiert ist durch -(Ci-C4)-Alkyl,-C (O) -O-RH or - (C 1 -C 4 ) alkylene-phenyl, wherein phenyl is unsubstituted or substituted by halogen, 4) - (C 0 -C 4) -alkylene-C (R 11) (R 12) - (C 3 -C 12) -cycloalkyl, where cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, 1, 7, 7 Trimethyl-bicyclo [3.1.13heptanyl, decahydronaphthalene, tetrahydronaphthalenyl, octahydro-4,7-methanoindenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently of one, two, three or four times is substituted by - (C 1 -C 4) -alkyl,
-C(O)-O-RH oder -(Ci-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch Halogen substituiert ist,-C (O) -O-RH or - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or substituted by halogen,
5) -(Crj-C4)-Alkylen-Het, wobei Het ausgewählt ist aus der Gruppe Acridinyl, Azepinyl, Azetidinyl, Aziridinyl, Benzimidazalinyl, Benzimidazolyl,5) - (Crj-C4) -alkylene-Het, wherein Het is selected from the group acridinyl, azepinyl, azetidinyl, aziridinyl, benzimidazalinyl, benzimidazolyl,
Benzo[1 ,3]dioxolyl, Benzofuranyl, Benzothiofuranyl, Benzothiophenyl, Benzoxazolyl, Benzthiazolyl, Benztriazolyl, Benztetrazolyl, Benzisoxazolyl, Benzisothiazolyl, Carbazolyl, 4aH-Carbazolyl, Carbolinyl, Chinazolinyl, Chinolinyl, 4H-Chinolizinyl, Chinoxalinyl, Chinuclidinyl, Chromanyl, Chromenyl, Cinnolinyl, Deca-hydrochinolinyl, Dibenzofuranyl, Dibenzothiophenyl,Benzo [1,3] dioxolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, Cinnolinyl, deca-hydroquinolinyl, dibenzofuranyl, dibenzothiophenyl,
Dihydrofuran[2,3-b]-tetrahydrofuranyl, Dihydrofuranyl, Dioxolyl, Dioxanyl, 2H, 6H-1 ,5,2-Dithiazinyl, Furanyl, Furazanyl, Imidazolidinyl, Imidazolinyl, Imidazolyl, 1 H-lndazolyl, Indolinyl, Indolizinyl, Indolyl, 3H-lndolyl, Isobenzofuranyl, Isochromanyl, Isoindazolyl, Isoindolinyl, Isoindolyl, Isochinolinyl (Benzimidazolyl), Isothiazolidinyl, 2-lsothiazolinyl, Isothiazolyl, Isoxazolyl,Dihydrofuran [2,3-b] tetrahydrofuranyl, dihydrofuranyl, dioxolyl, dioxanyl, 2H, 6H-1,2,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolidinyl, 2-isothiazolinyl, isothiazolyl, isoxazolyl,
Isoxazolidinyl, 2-lsoxazolinyl, Morpholinyl, Naphthyridinyl, Octahydroisochinolinyl, Oxadiazolyl, 1 ,2,3-Oxadiazolyl, 1 ,2,4-Oxadiazolyl, 1 ,2,5- Oxadiazolyl, 1 ,3,4-Oxadiazolyl, Oxazolidinyl, Oxazolyl, Oxazolidinyl, Oxothiolanyl, Pyrimidinyl, Phenanthridinyl, Phenanthrolinyl, Phenazinyl, Phenothiazinyl, Phenoxathiinyl, Phenoxazinyl, Phthalazinyl, Piperazinyl,Isoxazolidinyl, 2-isoxazolinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1, 2,3-oxadiazolyl, 1, 2,4-oxadiazolyl, 1, 2,5-oxadiazolyl, 1, 3,4-oxadiazolyl, oxazolidinyl, oxazolyl, Oxazolidinyl, oxothiolanyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,
Piperidinyl, Pteridinyl, Purynyl, Pyranyl, Pyrazinyl, Pyroazolidinyl, Pyrazolinyl, Pyrazolyl, Pyridazinyl, Pryidooxazolyl, Pyridoimidazolyl, Pyridothiazolyl, Pyridothiophenyl, Pyridinyl, Pyridyl, Pyrimidinyl, Pyrrolidinyl, Pyrrolinyl, 2H- Pyrrolyl, Pyrrolyl, Tetrahydrofuranyl, Tetrahydroisochinolinyl, Tetrahydrochinolinyl, Tetrahydropyridinyl, 6H-1 ,2,5-Thiadazinyl, 1 ,2,3-Piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl, 6H-1, 2,5-thiadazinyl, 1, 2,3-
Thiadiazolyl, 1 ,2,4-Thiadiazolyl, 1 ,2,5-Thiadiazolyl, 1 ,3,4-Thiadiazolyl, Thianthrenyl, Thiazolyl, Thienyl, Thienoimidazolyl, Thienooxazolyl, Thienopyridin, Thienothiazolyl, Thiomorpholinyl, Thiophenyl, Triazinyl, 1 ,2,3- Triazolyl, 1 ,2,3-Triazolyl, 1 ,2,4-Triazolyl, 1 ,2,5-Triazolyl, 1 ,3,4-Triazolyl und Xanthenyl, wobei Het oder Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch -(C-|-C4)-Alkyl substituiert ist 6) -(C<|-C6)-Alkylen-Phenyl, wobei Phenyl oder Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Halogen, Phenyl, -C(O)-O-RH , -(C-|-C4)-Alkyl-O-R11 , -O-(C<|-C4)-Alkyl oder -(C<|-C4)-Alkyl substituiert sind,Thiadiazolyl, 1, 2,4-thiadiazolyl, 1, 2,5-thiadiazolyl, 1, 3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienoimidazolyl, thienooxazolyl, Thienopyridine, thienothiazolyl, thiomorpholinyl, thiophenyl, triazinyl, 1, 2,3-triazolyl, 1, 2,3-triazolyl, 1, 2,4-triazolyl, 1, 2,5-triazolyl, 1, 3,4-triazolyl and Xanthenyl, wherein Het or alkylene is unsubstituted or independently of one another monosubstituted or disubstituted by - (C 1 -C 4) -alkyl 6) - (C 1 -C 6) -alkylene-phenyl, where phenyl or alkylene is unsubstituted or independent of one another mono- or disubstituted by halogen, phenyl, -C (O) -O-RH, - (C 1 -C 4) -alkyl-O-R 11, -O- (C 1 -C 4) -alkyl or - (C <| -C 4 ) -alkyl are substituted,
7) -(Crj-C4)-Alkylen-C(R11 )(R12)-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch Phenyl oder Fluor substituiert ist,7) - (Crj-C4) -alkylene-C (R11) (R12) -phenyl, where phenyl is unsubstituted or independently of one another monosubstituted, disubstituted or trisubstituted by phenyl or fluorine,
8) 1 ,2,3,4-Tetrahydro-naphthalenyl,8) 1, 2,3,4-tetrahydro-naphthalenyl,
9) -(C0-C4)-Alkylen-CH(R11 )-C(O)-NH2,9) - (C 0 -C 4) -alkylene-CH (R 11) -C (O) -NH 2,
10) -(C0-C4)-Alkylen-CH(R1 I)-C(O)-N H-(C 1-C4)-Alkyl, 11) -(C0-C4)-Alkylen-CH(R11)-C(O)-NH-CH(R12)-R13,10) - (C 0 -C 4 ) -alkylene-CH (R 1 I) -C (O) -N H- (C 1 -C 4 ) -alkyl, 11) - (C 0 -C 4 ) -alkylene-CH (R11) -C (O) -NH-CH (R12) -R13,
12) -(Ci-C6)-AIkylen-C(O)-O-R11, wobei Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Halogen, Phenyl, -C(O)-O-RH , -(C-i-C^-Alkyl-O-RH , -O-(C<|-C4)-Alkyl oder -(C<|-C4)-Alkyl substituiert ist, 13) -(Co-C4)-Alkylen-C(R11)(R12)-C(O)-O-R11 , oder12) - (C 1 -C 6) -alkylene-C (O) -O-R 11, where alkylene is unsubstituted or independently of one another by halogen, phenyl, -C (O) -O-RH, - (C 1 -C 4) - Alkyl-O-RH, -O- (C 1 -C 4 ) -alkyl or - (C 1 -C 4 ) -alkyl, 13) - (C 0 -C 4 ) -alkylene-C (R 11) (R 12 ) -C (O) -O-R11, or
14) -(C-j-C3)-Fluoralkyl, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom an das sie gebunden sind einen Mono- oder Bicyclischen Ring bilden ausgewählt aus der Gruppe Pyrrolidin, Piperidin, 2-Aza-bicyclo[3.2.2]nonan und 7-Aza-bicyclo[2.2.1]hep-tan, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(C<|-C4)-Alkyl, -14) - (Cj-C3) -Fluoralkyl, or the two radicals R6 together with the N-atom to which they are attached form a mono- or bicyclic ring selected from the group pyrrolidine, piperidine, 2-azabicyclo [ 3.2.2] nonane and 7-azabicyclo [2.2.1] hep-tane, where the ring is unsubstituted or mono- or disubstituted by - (C 1 -C 4) -alkyl,
C(O)-O-RH , -(C-|-C4)-Alkyl-O-R11 oder Phenyl substituiert ist, R7 für Wasserstoffatom oder -(Ci-C4)-Alkyl steht, R9 für Wasserstoffatom oder -(C-|-C4)-Alkyl steht,C (O) -O-RH, - (C-C4) -alkyl-O-R11 or phenyl, R7 is hydrogen or - (Ci-C4) alkyl, R9 is hydrogen or - (C-) C 1 -C 4) -alkyl,
R11 und R12 gleich oder verschieden sind und unabhängig voneinander für 1) Wasserstoffatom, 2) -(C-i-C^-Alkyl,R 11 and R 12 are identical or different and independently of one another represent 1) hydrogen atom, 2) - (C 1 -C 4) alkyl,
3) -(C()-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch -OH, Halogen oder -O-(C-|-C4)-Alkyl substituiert ist, 4) -(Crj-C4)-Alkylen-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adaman- tanyl, 1 ,7,7-Trimethyl-bicyclo[3.1.1]heptanyl, Decahydro-naphthalenyl, Tetrahydronaphthalenyl, Octahydro-4,7-methano-indenyl oder Bicyclo[2.2.1]- heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch -(C-|-C4)-Alkyl, -C(O)-O-RI 3 oder Phenyl substituiert ist, oder3) - (C () - C4) -alkylene-phenyl, wherein phenyl is unsubstituted or substituted independently of one another once, twice or three times by -OH, halogen or -O- (C 1 -C 4) -alkyl, 4 ) - (j Cr C4) -alkylene- (C3-Ci2) -cycloalkyl, wherein cycloalkyl is selected from the group consisting cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantane tanyl, 1, 7,7-trimethyl-bicyclo [3.1. 1] heptanyl, decahydro-naphthalenyl, tetrahydronaphthalenyl, octahydro-4,7-methano-indenyl or bicyclo [2.2.1] -heptanyl and in which cycloalkyl is unsubstituted or independently of one another once, twice, three or four times by - (C-) C 1 -C 4) -alkyl, -C (O) -O-RI 3 or phenyl, or
5) -(Cn-C4)-Alkylen-Indolyl, stehen,5) - (Cn-C4) -alkylene-indolyl,
R13 für 1 ) Wasserstoffatom,R 13 is 1) hydrogen,
2) -(C^J-Alkyl, 3) -(C0-C4)-Alkylen-C(O)-O-R14,2) - (C 1 -C 4 alkyl, 3) - (C 0 -C 4 ) alkylene-C (O) -O-R 14,
4) -(C0-C4)-Alkylen-C(O)-R14 oder4) - (C 0 -C 4 ) -alkylene-C (O) -R 14 or
5) -(Cn-C4)-Alkylen-O-R 14 steht,5) - (Cn-C 4 ) -alkylene-OR 14,
R14 für Wasserstoffatom, -(C<|-C4)-Alkyl, -NH2 oder -OH steht und R15 für Wasserstoff atom, -(C-|-C4)-Alkyl, -0-CF3, -NH2, -OH, -CF3 oder Halogen steht.R 14 is hydrogen, - (C 1 -C 4 ) -alkyl, -NH 2 or -OH and R 15 is hydrogen, - (C 1 -C 4 ) -alkyl, -O-CF 3 , -NH 2, -OH , -CF3 or halogen.
Die Erfindung betrifft auch die Verwendung der Verbindung der Formel I, wobei X für -SO2- steht, R1 für 1) Wasserstoffatom oder 2) -(C-I -C4)-Alkyl, steht,The invention also relates to the use of the compound of the formula I in which X is -SO 2 -, R 1 is 1) hydrogen or 2) - (C 1 -C 4) -alkyl,
R2 für 1) -(C1-C6)-Alkylen-NH2,R 2 for 1) - (C 1 -C 6) -alkylene-NH 2,
2) -(C1-C4)-Alkylen-Pyridyl-NH2,2) - (C 1 -C 4 ) -alkylene-pyridyl-NH 2,
3) -(C-|-C4)-Alkylen-Piperidinyl-NH2,3) - (C 1 -C 4) -alkylene-piperidinyl-NH 2,
4) -(C1-C4)-Alkylen-NH-C(=NH)-NH2, 5) -(C1-C6)-Alkylen-NH-C(=NH)-(C1-C4)-Alkyl,4) - (C 1 -C 4) -alkylene-NH-C (= NH) -NH 2 , 5) - (C 1 -C 6 ) -alkylene-NH-C (= NH) - (C 1 -C 4 ) -alkyl,
6) -(Ci-C4)-Alkylen-(C3-C6)-Cycloalkyl-NH2,6) - (C 1 -C 4) -alkylene- (C 3 -C 6) -cycloalkyl-NH 2,
7) -(Ci-C4)-Alkylen-O-NH-C(=NH)-NH2> 7) - (C 1 -C 4 ) -alkylene-O-NH-C (= NH) -NH 2>
8) -(C1-C6)-Alkylen-NH-C(O)-O-(C1-C4)-Alkylen-Phenyl, 9) -(C-I -C4)-Alkyien-N H-C(O)-(C i-Ce)-Alkyl oder8) - (C 1 -C 6 ) -alkylene-NH-C (O) -O- (C 1 -C 4 ) -alkylene-phenyl, 9) - (CI-C 4 ) -alkyiene-N HC (O ) - (C i -C 6) alkyl or
10) -(Ci-C4)-Alkylen-Phenyl-NH2,10) - (C 1 -C 4) -alkylene-phenyl-NH 2,
11) -(C1 -02J-AIkVIeIi-SO2-(C1 -C4)-Alkylen-NH2, oder11) - (C 1 -O 2 -alkyl-SO 2 - (C 1 -C 4 ) -alkylene-NH 2 , or
12) -(C1-C2)-Alkylen-S-(C1-C4)-Alkylen-NH2, steht, R3 für 1) -(C-i-C^-Alkyl, 2) -(C1-C4)-Alkylen-(C3-C6)-Cycloalkyl,12) - (C 1 -C 2 ) -alkylene-S- (C 1 -C 4 ) -alkylene-NH 2, R 3 is 1) - (C 1 -C 4 -alkyl, 2) - (C 1 -C 4 ) alkylene- (C3-C6) -cycloalkyl,
3) -(C-|-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch -OH substituiert ist,3) - (C 1 -C 4 ) -alkylene-phenyl, where phenyl is unsubstituted or substituted by -OH,
4) -(C1 -Ce)-AIkVIeH-NH-C(O)-O-(C1 -C4)-Alkylen-Phenyl,4) - (C 1 -Ce) -AlkVIeH-NH-C (O) -O- (C 1 -C 4 ) -alkylene-phenyl,
5) Wasserstoffatom steht, R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander für5) is hydrogen, R4 is -N (R6) 2 , where R6 are the same or different and independently of one another
1) Wasserstoffatom,1) hydrogen atom,
2) -(C1-Ce)-AIkVl,2) - (C 1 -Ce) -AlkVl,
3) -(Cn.-C4)-Alkylen-(C3-C8)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclopropyl, Adamantanyl, 1 ,7,7-3) - (C 1 -C 4 ) -alkylene- (C 3 -C 8) -cycloalkyl, where cycloalkyl is selected from the group consisting of cyclohexyl, cyclopentyl, cyclopropyl, adamantanyl, 1, 7,7-
Trimethyl-bicyclo[3.1.1]heptanyl, Decahydro-naphthalen, Octahydro-4,7- methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch -(C-|-C4)-Alkyl oder Phenyl substituiert ist, 4) -C(R11)(R12)-Adamantanyl,Trimethyl-bicyclo [3.1.1] heptanyl, decahydro-naphthalene, octahydro-4,7-methano-indenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently of one another mono-, di- or trisubstituted by - (C-) C 1 -C 4 ) -alkyl or phenyl, 4) -C (R 11) (R 12) -adamantanyl,
5) -CH(R11)-C(O)-NH-CH(R12)-R13,5) -CH (R11) -C (O) -NH-CH (R12) -R13,
6) -(Co-C4)-Alkylen-Het, wobei Het ausgewählt ist aus der Gruppe6) - (Co-C 4 ) -alkylene-Het, wherein Het is selected from the group
Benzimidazolyl, Isoxazolyl, Piperidin, Pyridin, Pyrrolidinyl, Thiophenyl und Benzo[1 ,3]dioxol, 7) 1 ,2,3,4-Tetrahydro-naphthalenyl, 8) -(Co-C4)-Alkylen-C(R11 )(R12)-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch Phenyl oder Fluor substituiert ist,Benzimidazolyl, isoxazolyl, piperidine, pyridine, pyrrolidinyl, thiophenyl and benzo [1,3] dioxole, 7) 1,2,3,4-tetrahydro-naphthalenyl, 8) - (Co-C4) -alkylene-C (R11) (R12) -phenyl, where phenyl is unsubstituted or independently of one another mono-, di- or trisubstituted by phenyl or fluorine,
9) -CH(RH)-C(O)-NH2, 10) -CH(RI 1)-C(O)-NH-CH(R12)-CH2-OH,9) -CH (RH) -C (O) -NH 2 , 10) -CH (RI 1) -C (O) -NH-CH (R 12) -CH 2 -OH,
11) -(C-|-C6)-Alkylen-Phenyl, wobei Phenyl oder Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Chlor, Fluor, -C(O)-O-RH , -(C<|-C4)-Alkyl-O-R11 , -O-(C<i-C4)-Alkyl, Phenyl oder -(C-|-C4)-Alkyl substituiert sind, 12) -CH(RI I)-C(O)-N H-(C i-C4)-Alkyl,11) - (C 1 -C 6) -alkylene-phenyl, where phenyl or alkylene is unsubstituted or independently of one another by chlorine, fluorine, -C (O) -O-RH, - (C <| -C 4) -Alkyl-O-R11, -O- (C <i-C4) -alkyl, phenyl or - (C-C4) -alkyl, 12) -CH (RI I) -C (O) -N H (C 1 -C 4) -alkyl,
13) -(C0-C4)-Alkylen-C(R11)(R12)-Bicyclo[3.1.1]heptanyl, wobei13) - (C 0 -C 4 ) -alkylene-C (R 11) (R 12) -bicyclo [3.1.1] heptanyl, wherein
Bicyclo[3.1.1]heptanyl unsubstituiert oder ein- bis vierfach durch -(C-|-C4)-Alkyl substituiert ist,Bicyclo [3.1.1] heptanyl is unsubstituted or substituted one to four times by - (C 1 -C 4) -alkyl,
14) -(C-|-C6)-Alkylen-C(O)-O-R11 , wobei Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Chlor, Fluor,14) - (C 1 -C 6) -alkylene-C (O) -O-R 11, where alkylene is unsubstituted or independently of one another by chlorine, fluorine,
-C(O)-O-RH , -(C<|-C4)-Alkyl-O-R11 , -O-(Ci-C4)-Alkyl, Phenyl oder-C (O) -O-RH, - (C 1 -C 4) -alkyl-O-R 11, -O- (C 1 -C 4 ) -alkyl, phenyl or
-(C-j-C4)-Alkyl substituiert ist,- (C 1 -C 4) -alkyl is substituted,
15) -(C0-C4)-Alkylen-C(R11 )(R12)-C(O)-O-R11 , oder15) - (C 0 -C 4 ) -alkylene-C (R 11) (R 12) -C (O) -O-R 11, or
16) -CH2-CF2-CF3, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom an das sie gebunden sind einen Mono- oder Bicyclischen Ring bilden, ausgewählt aus der Gruppe Pyrrolidine, 2-aza-bicyclo[3.2.2]nonan und 7-aza-bicyclo[2.2.1]heptan, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(C-|-C4)-Alkyl,16) -CH 2 -CF 2 -CF 3 , or the two radicals R 6 together with the N-atom to which they are attached form a mono- or bicyclic ring selected from the group consisting of pyrrolidines, 2-azabicyclo [ 3.2.2] nonane and 7-aza-bicyclo [2.2.1] heptane, where the ring is unsubstituted or mono- or disubstituted by - (C 1 -C 4) -alkyl,
-C(O)-O-RH , -(C<|-C4)-Alkyl-O-R11 oder Phenyl substituiert ist, R7 für Wasserstoffatom oder -(C-|-C4)-Alkyl steht, R9 für Wasserstoffatom oder -(C-|-C4)-Alkyl steht,C (O) -O-RH, - (C 1 -C 4) -alkyl-O-R 11 or phenyl, R 7 is hydrogen or - (C 1 -C 4) -alkyl, R 9 is hydrogen or (C 1 -C 4) -alkyl,
R11 und R12 gleich oder verschieden sind und unabhängig voneinander fürR11 and R12 are the same or different and independently of each other
1 ) Wasserstoffatom ,1) hydrogen atom,
2) -(C1-C4)-Alkyl, 3) -(Co-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch -OH, Halogen oder -O-(Ci-C4)-Alkyl substituiert ist,2) - (C 1 -C 4 ) -alkyl, 3) - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or independently of one another mono-, di- or trisubstituted by -OH, halogen or -O- (C 1 -C 4 ) -alkyl,
4) -(C()-C4)-Alkylen-(C3-C-|2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adamantanyl,4) - (C () - C4) -alkylene- (C3-C- | 2) -cycloalkyl, where cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl,
1,7,7-Trimethyl-bicyclo[3.1.1]heptanyl, Decahydro-naphthalenyl, Octahydro-4,7- methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch -(C1-C4)-1,7,7-trimethyl-bicyclo [3.1.1] heptanyl, decahydro-naphthalenyl, octahydro-4,7-methano-indenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently of one another, two-, three or four times by - (C 1 -C 4 ) -
Alkyl, -C(O)-O-RI 3 oder Phenyl substituiert ist, oder 5) -(Crj-C4)-Alkylen-lndolyl, stehen,Alkyl, -C (O) -O-RI 3, or phenyl, or 5) - (Cr j -C 4) -alkylene-indolyl, stand,
R13 für 1 ) Wasserstoff atom,R13 for 1) hydrogen atom,
2) -(C1-C4J-AIkVl1 2) - (C 1 -C 4 J-AlkVl 1
3) -(C0-C4)-Alkylen-C(O)-O-R14,3) - (C 0 -C 4 ) -alkylene-C (O) -O-R 14,
4) -(C0-C4)-Alky!en-C(O)-R14 oder 5) -(Crj-C4)-Alkylen-O-R14 steht,4) - (C 0 -C 4) -Alky en-C (O) -R 14 or 5) - (j Cr C4) -alkylene-O-R14,
R14 für Wasserstoffatom, -(Ci-C4)-Alkyl, -NH2 oder -OH steht und R15 für Wasserstoff atom, -(C-|-C4)-Alkyl, -0-CF3, -NH2, -OH, -CF3 oder Halogen steht.R14 is hydrogen atom, is - (Ci-C 4) alkyl, -NH 2 or -OH, and R15 is hydrogen atom, - (C- | -C4) alkyl, -0-CF 3, -NH 2, -OH , -CF3 or halogen.
Die Erfindung betrifft auch die Verbindung der Formel I und/oder einer stereoisomeren Form der Verbindung der Formel I und/oder Gemische dieser Formen in jedem Verhältnis, und/oder ein physiologisch verträgliches Salz derThe invention also relates to the compound of formula I and / or a stereoisomeric form of the compound of formula I and / or mixtures of these forms in any ratio, and / or a physiologically acceptable salt of
Verbindung der Formel I, wobeiA compound of the formula I, wherein
X für -C(O)- steht, R1 für 1) Wasserstoff atom,X is -C (O) -, R1 is 1) hydrogen atom,
2) -(C1-Ce)-AIkVl,2) - (C 1 -Ce) -AlkVl,
3) -(Co-C4)-Alkylen-(C3-C12)-Cycloalkyl oder3) - (Co-C4) -alkylene- (C3-C1 2) cycloalkyl, or
4) -(C -i -C6)-Alkylen-(Ce-C 14)-Aryl steht,4) - (C 1 -C 6) -alkylene- (Ce-C 14) -aryl,
R2 für den Rest der Formel Il -(A1)m-A2 (II) steht, worin m die ganze Zahl Null oder 1 bedeutet,R2 for the rest of the formula II - (A1) m -A2 (II) where m is the integer zero or 1,
A1 für 1) -(CH2)rr- worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet,A1 for 1) - (CH2) rr - where n is the integer zero, 1, 2 or 3,
2) -NH-(CH2)n-, worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet, 3) -NH(C-|-C6)-Alkyl)-(CH2)n-, worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet,2) -NH- (CH 2) n -, wherein n is the integer zero, 1, 2 or 3, 3) -NH (C 1 -C 6 ) alkyl) - (CH 2) n -, wherein n is the integer zero, 1, 2 or 3 means
4) -NH((C3-C6)-Cycloalkyl)-(CH2)rr. worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet,4) -NH ((C 3 -C 6) -cycloalkyl) - (CH 2) rr. where n is the integer zero, 1, 2 or 3,
5) -O-(CH2)rr> worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet, oder 6) -(CH2)n-SOx-, worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet und x die ganze Zahl Null, 1 oder 2 bedeutet, steht, A2 für 1) Het, wobei unter Het ein 4- bis 15-gliedriges heterocyclisches5) -O- (CH 2) rr > wherein n is the integer zero, 1, 2 or 3, or 6) - (CH 2) n -SO x -, wherein n is the integer zero, 1, 2 or 3 and x is the integer zero, 1 or 2, A2 is 1) Het, wherein Het is a 4- to 15-membered heterocyclic
Ringsystem mit 4 bis 15 Ringatomen verstanden wird, die in ein, zwei oder drei miteinander verbundenen Ringsystemen vorliegen und die ein, zwei, drei oder vier gleiche oder verschiedene Heteroatome aus der Reihe Sauerstoff,Ring system comprising 4 to 15 ring atoms which are present in one, two or three interconnected ring systems and which contain one, two, three or four identical or different heteroatoms from the series oxygen,
Stickstoff oder Schwefel enthalten und unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch ein -(C-|-C3)-Alkyl, Halogen, -NH2,Contain nitrogen or sulfur and are unsubstituted or independently of one another mono-, di- or trisubstituted by a - (C 1 -C 3) -alkyl, halogen, -NH 2,
CF3 oder -O-CFß substituiert ist,CF3 or -O-CF3 is substituted,
2) -(C0-C6)-Alkylen-NH2, 3) -(Ci-C6)-Alkylen-NH-C(=NH)-NH2> 2) - (C 0 -C 6 ) -alkylene-NH 2 , 3) - (C 1 -C 6 ) -alkylene-NH-C (= NH) -NH 2>
4) -(Ci-C6)-Alkylen-NH-C(=NH)-(C1-C4)-Alkyl,4) - (C 1 -C 6 ) -alkylene-NH-C (NHNH) - (C 1 -C 4 ) -alkyl,
5) -(Co-C4)-Alkylen-0-NH-C(=NH)-NH2i 5) - (Co-C 4 ) -alkylene-0-NH-C (= NH) -NH 2i
6) -(Co-C4)-Alkylen-NH-C(O)-(C1-C6)-Alkyl,6) - (Co-C 4 ) -alkylene-NH-C (O) - (C 1 -C 6 ) -alkyl,
7) -(Ci-CeJ-Alkylen-NH-C^J-O-CC-i^J-Alkylen-Aryl, wobei Aryl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist,7) - (Ci-CeJ-alkylene-NH-C ^ JO-CC-i ^ J-alkylene-aryl, wherein aryl is unsubstituted or substituted by -NH2 or substituted by -NH2 and one, two or three times by R15 is
8) -(C3-C8)-Cycloalkyl-NH2, oder8) - (C 3 -C 8 ) -cycloalkyl-NH 2 , or
9) -(Co-C4)-Alkylen-(C6-C<]4)-Aryl, wobei Aryl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist, steht, R3 für 1) -(Ci-C6)-Alkyl,9) - (C 1 -C 4) -alkylene- (C 6 -C 4] -aryl, where aryl is unsubstituted or substituted by -NH 2 or substituted by -NH 2 and mono-, di- or trisubstituted by R 15, R 3 is 1) - (C 1 -C 6) -alkyl,
2) -(Co-C4)-Alkylen-(C3-C12)-Cycloalkyl,2) - (Co-C4) alkylene- (C3-C12) -cycloalkyl,
3) -(C-|-Cg)-Alkylen-(C6-C-|4)-Aryl, wobei Aryl unabhängig voneinander ein-3) - (C 1 -C 6) -alkylene- (C 6 -C 4) -aryl, where aryl independently of one another
, zwei- oder dreifach durch R15 substituiert ist, 4) -(C0-C8)-Alky!en-N(R5)-PG,which is substituted twice or three times by R 15, 4) - (C 0 -C 8 ) -alkyl-N (R 5) -PG,
5) -(Ci-CßJ-Alkylen-NH-CCOJ-O-CCT-C^-Alkylen-Aryl, wobei Aryl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,5) - (Ci-CβJ-alkylene-NH-CCOJ-O-CCT-C ^ alkylene-aryl, wherein aryl is independently substituted one, two or three times by R15,
6) -(Co-C4)-Alkylen-(C6-Ci4)-Aryl-(Co-C4)-Alkylen-N(R5)-PG,6) - (C o -C 4) alkylene- (C6-Ci4) aryl (Co-C4) -alkylene-N (R5) -PG,
7) -(C0-C8)-Alkylen-O-PG, 8) -(C0-C4)-Alkylen-(C6-C-i4)-Aryl-(Co-C4)-Alkylen-0-PG,7) - (C 0 -C 8) -alkylene-O-PG, 8) - (C 0 -C 4) -alkylene- (C 6 -C 14) -aryl (Co-C 4) -alkylene-0-PG,
9) -(Cn-C8)-Alkylen-C(O)-O-PG,9) - (Cn-C8) -alkylene-C (O) -O-PG,
10) -(Co-C4)-Alkylen-(C6-C14)-Aryl-(Co-C4)-Aikylen-C(O)-0-PG oder10) - (Co-C4) alkylene- (C6-C14) aryl (Co-C4) -Aikylen-C (O) -0-PG or
11) Wasserstoffatom, steht, R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander für11) hydrogen, R4 is -N (R6) 2, where R6 are the same or different and independently of one another
1) Wasserstoffatom,1) hydrogen atom,
2) -(Ci-C^-Alkyl,2) - (C 1 -C 4) -alkyl,
3) -(Cn-C4)-Alkylen-(C3-C-|2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R11 , Halogen, -C(O)-O-R11 , -(C-|-C4)-Alkyl-O-R11 oder -O-(Ci-C4)-Alkyl substituiert ist,3) - (Cn-C4) -alkylene- (C3-C- | 2) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently one, two, three or four times by R11, halogen, -C (O) -O R 11 is substituted by (C 1 -C 4) -alkyl-O-R 11 or -O- (C 1 -C 4) -alkyl,
4) -(Co-C6)-Alkylen-(C6-C-|4)-Aryl, wobei Aryl und Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R11 , Halogen, -C(O)-O-RH , -(Ci-C4)-Alkyl-O-R11 , -C(O)-N(R8)2 oder -O-(C-|-C-4)-Alkyl substituiert sind,4) - (Co-C6) -alkylene- (C6-C- | 4) -aryl, where aryl and alkylene are unsubstituted or independently of one another once, twice, three or four times by R11, halogen, -C (O) -O-RH, - (C 1 -C 4 ) -alkyl-O-R 11, -C (O) -N (R 8) 2 or -O- (C 1 -C 4) -alkyl,
5) -(C0-C8)-Alkylen-N(R5)-PG,5) - (C 0 -C 8 ) -alkylene-N (R 5) -PG,
6) -(Co-C4)-Alkylen-(C6-Ci4)-Aryl-(Co-C4)-Alkyl-N(R5)-PG,6) - (Co-C 4 ) -alkylene- (C 6 -C 14) -aryl (Co-C 4 ) -alkyl-N (R 5) -PG,
7) -(C0-C8)-Alkylen-O-PG,7) - (C 0 -C 8) -alkylene-O-PG,
8) -(Co-C4)-Alkylen-(C6-C14)-Aryl-(Co-C4)-Alkyl-O-PG, 9) -(Co-C8)-Alkylen-C(O)-O-R11 ,8) - (Co-C4) alkylene- (C6-C14) aryl (Co-C4) -alkyl-O-PG, 9) - (Co-C8) -alkylene-C (O) -O-R11,
10) -(C0-C4)-Alkylen-(C6-Ci4)-Aryl-(Co-C4)-Alkyl-C(0)-O-PG,10) - (C 0 -C 4 ) -alkylene- (C 6 -C 14) -aryl (C 1 -C 4 ) -alkyl-C (O) -O-PG,
11) -(Co-C4)-Alkylen-Het, wobei unter Het ein 4- bis 15-gliedriges heterocyclisches Ringsystem verstanden wird mit 4 bis 15 Ringatomen, die in ein, zwei oder drei miteinander verbundenen Ringsystemen vorliegen und die ein, zwei, drei oder vier gleiche oder verschiedene Heteroatome aus der Reihe Sauerstoff, Stickstoff oder Schwefel enthalten, wobei Het oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-RH , -(C<|-C4)-Alkyl-O-R11 oder -O-(C-|-C4)-Alkyl substituiert sind,11) - (Co-C4) -alkylene-Het, where Het is a 4- to 15-membered heterocyclic ring system is understood with 4 to 15 ring atoms, which are present in one, two or three interconnected ring systems and the one, two, contain three or four identical or different heteroatoms from the series oxygen, nitrogen or sulfur, wherein Het or alkylene is unsubstituted or independently of one another once, twice or three times by R11, halogen, -C (O) -O-RH, - (C <C 1 -C 4) -alkyl-O-R 11 or -O- (C 1 -C 4) -alkyl,
12) -(C-i-C3)-Fluoralkyl,12) - (C-i-C3) fluoroalkyl,
13) -(C0-C4)-Alkylen-CH(R11 )-C(O)-NH2,13) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH 2 ,
14) -(C0-C4)-Alkylen-CH(R11)-C(O)-NH-(Ci-C4)-Aikyl,14) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH- (C 1 -C 4 ) -acyl,
15) -(C0-C4)-Alkylen-CH(R11)-C(O)-NH-CH(R12)-R13, oder 16) Aminosäure, wobei die Bindung der Aminosäure über eine Peptid-15) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH-CH (R 12) -R 13, or 16) amino acid, wherein the binding of the amino acid via a peptide
Bindung erfolgt und der Carboxyl-Rest der Aminosäure unsubstituiert oder durch PG oder durch -N(R5)2 substituiert ist, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom, an das sie gebunden sind, einen mono- oder bicyclischen Ring mit 4 bis 9 Ringatomen bilden, der gesättigt, teilweise gesättigt oder aromatisch ist, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(C-|-C4)-Alkyl, -C(O)-O-R11 ,Binding takes place and the carboxyl radical of the amino acid is unsubstituted or substituted by PG or by -N (R5) 2, or the two radicals R6 together with the N-atom to which they are attached, a mono- or bicyclic ring with 4 to 9 ring atoms which is saturated, partially saturated or aromatic, the ring being unsubstituted or mono- or disubstituted by - (C 1 -C 4) -alkyl, -C (O) -O-R 11,
Halogen, -(Ci-C4)-Alkyl-O-R11 oder Phenyl substituiert ist, R5 für Wasserstoffatom oder-(C-|-C6)-Alkyl steht,Halogen, (C 1 -C 4) -alkyl-O-R 11 or phenyl, R 5 is hydrogen or (C 1 -C 6) -alkyl,
PG für eine Schutzgruppe für die Amino-, Carboxyl- oder für die Hydroxyfunktion steht,PG is a protective group for the amino, carboxyl or for the hydroxyl function,
R7 für Wasserstoffatom oder -(C-|-C6)-Alkyl steht,R 7 is hydrogen or - (C 1 -C 6) -alkyl,
R8 für Wasserstoffatom oder -(C-|-C6)-Alkyl steht, R9 für Wasserstoffatom oder -(Ci-Ce)-Alkyl steht,R 8 is hydrogen or - (C 1 -C 6) -alkyl, R 9 is hydrogen or - (C 1 -C 6) -alkyl,
R11 und R12 gleich oder verschieden sind und unabhängig voneinander für 1) Wasserstoffatom, 2) -(C1-Ce)-AIkYl,R 11 and R 12 are identical or different and independently of one another represent 1) hydrogen atom, 2) - (C 1 -Ce) -Alkyl,
3) -(C()-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder oder unabhängig voneinander ein-, zwei- oder dreifach durch Halogen, -OH oder -O-(Ci-C4)-Alkyl substituiert ist, 4) -(Co-C4)-Alkylen-(C3-C-|2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R13, Halogen, -C(O)-O-R13, -(Ci-C4)-Alkyl-O-R13, -O-(Ci-C4)-Alkyl oder -(Crj-C-4)-Alkylen-Phenyl substituiert ist,3) - (C () - C4) -alkylene-phenyl, where phenyl is unsubstituted or independently or monosubstituted, disubstituted or trisubstituted by halogen, -OH or -O- (C 1 -C 4) -alkyl, 4) - (Co-C4) -alkylene- (C3-C- | 2) -cycloalkyl, wherein cycloalkyl unsubstituted or independently of one another once, twice, three or four times by R13, halogen, -C (O) -O-R13 , - (Ci-C4) -alkyl-O-R13, -O- (Ci-C4) -alkyl or - (Cr j -C 4) -alkylene-phenyl,
5) -(C0-C4)-Alkylen-C(O)-N(R13)2 oder 6) -(Cn-C4)-A!kylen-Indolyl, stehen,5) - (C 0 -C 4 ) -alkylene-C (O) -N (R 13) 2 or 6) - (C 1 -C 4 ) -alkylene-indolyl,
R13 für 1 ) Wasserstoffatom,R 13 is 1) hydrogen,
2) .(d-C^-Alkyl,2) . (DC ^ alkyl,
3) -(C0-C4)-Alkylen-C(O)-O-R14,3) - (C 0 -C 4 ) -alkylene-C (O) -O-R 14,
4) -(Co-C4)-Alkylen-C(O)-R14 oder 5) -(C0-C4)-Alkylen-O-R 14 steht,4) - (Co-C4) -alkylene-C (O) -R14 or 5) - (C 0 -C4) -alkylene-OR 14,
R14 für Wasserstoffatom, -(C-|-C4)-Alkyl, -NH2 oder -OH, steht und R15 für Wasserstoffatom, -(Ci-C4)-Alkyl, -0-CF3, -NH2, -OH, -CF3 oder Halogen steht.R 14 is hydrogen, - (C 1 -C 4 ) -alkyl, -NH 2 or -OH, and R 15 is hydrogen, - (C 1 -C 4 ) -alkyl, -O-CF 3 , -NH 2 , -OH, -CF 3 or halogen.
Die Erfindung betrifft auch die Verbindung der Formel I, wobei X für -C(O)- steht, R1 für 1) Wasserstoffatom oderThe invention also relates to the compound of formula I wherein X is -C (O) -, R1 is 1) hydrogen or
2) -(C-i^-Alkyl, steht,2) - (C 1 -C 4) alkyl,
R2 für 1) -(C1-C6)-Alkylen-NH2, 2) -(Co-C4)-Alkylen-Pyridyl-NH2,R 2 for 1) - (C 1 -C 6) -alkylene-NH 2 , 2) - (Co-C 4 ) -alkylene-pyridyl-NH 2 ,
3) -(C0-C4)-Alkylen-Piperidinyl-NH2,3) - (C 0 -C 4) -alkylene-piperidinyl-NH 2,
4) -(Cfj-C4)-Alkylen-Thiazolyl-NH2,4) - (Cfj-C4) -alkylene-thiazolyl-NH2,
5) -(Ci-C6)-Alkylen-NH-C(=NH)-NH2,5) - (C 1 -C 6) -alkylene-NH-C (= NH) -NH 2,
6) -(Co-C4)-Alkylen-(C3-C8)-Cycloalkyl-NH2, 7) -(C 1 -C6)-Alkylen-N H-C(=N H)-(C -j -C4)-Alkyl ,6) - (Co-C4) -alkylene- (C3-C8) -cycloalkyl-NH2, 7) - (C 1 -C 6) -alkylene-N HC (= NH) - (C 1 -C 4 ) -alkyl,
8) -(Co-C4)-Alkylen-O-NH-C(=NH)-NH2,8) - (Co-C 4 ) -alkylene-O-NH-C (= NH) -NH 2,
9) -(Ci-C6)-Alkylen-NH-C(O)-O-(C-|-C4)-Alkylen-Aryl, wobei Aryl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist,9) - (C 1 -C 6) -alkylene-NH-C (O) -O- (C 1 -C 4) -alkylene-aryl, wherein aryl is unsubstituted or substituted by -NH 2 or by -NH 2 and one, two or is substituted by R15 in triplicate,
10) -(Co-C4)-Alkylen-NH-C(0)-(Ci-C4)-Alkyl,10) - (Co-C 4 ) -alkylene-NH-C (O) - (C 1 -C 4 ) -alkyl,
11) -(Co-C4)-Alkylen-(C6-C<|4)-Aryl, wobei Aryl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist, oder 12) -(Ci-C4)-Alkylen-SOχ-(C-t-C4)-Alkylen-NH2 worin x die ganze Zahl Null,11) - (C 1 -C 4 ) -alkylene- (C 6 -C 4 ) -aryl, wherein aryl is unsubstituted or substituted by -NH 2 or substituted by -NH 2 and mono-, di- or trisubstituted by R 15, or 12) - (C 1 -C 4 ) -alkylene-SOχ- (CtC 4 ) -alkylene-NH 2 where x is the integer zero,
1 oder 2 bedeutet, steht, R3 für 1) -(C<|-C4)-A!kyl,1 or 2, R3 is 1) - (C <C- 4 ) -alkyl,
2) -(C0-C4)-Alkylen-(C3-C8)-Cycloalkyl,2) - (C 0 -C 4 ) -alkylene- (C 3 -C 8 ) -cycloalkyl,
3) -(C<|-C6)-Alkylen-Aryl, wobei Aryl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,3) - (C 1-C 6) -alkylene-aryl, where aryl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15,
4) -(Ci-C6)-Alkylen-NH-C(O)-O-(C1-C4)-Alkylen-Aryl, wobei Aryl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,4) - (C 1 -C 6 ) -alkylene-NH-C (O) -O- (C 1 -C 4 ) -alkylene-aryl, where aryl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15,
5) -(C1-C6)-Alkylen-NH-PG,5) - (C 1 -C 6) -alkylene-NH-PG,
6) -(C<|-C6)-Alkylen-O-PG, 7) -(C-I -CßJ-Alkyl, oder6) - (C 1-C 6) -alkylene-O-PG, 7) - (C 1 -C 6) -alkyl, or
8) Wasserstoffatom, steht, wobei PG für t-Butyl-, t-Butyloxycarbonyl oder Benzyloxycarbonyl steht, R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander für 1) Wasserstoffatom,8) hydrogen, where PG is t-butyl, t-butyloxycarbonyl or benzyloxycarbonyl, R4 is -N (R6) 2, where R6 are identical or different and independently of one another represent 1) hydrogen atom,
2) -(Ci-CeO-Alkyl,2) - (C 1 -C 10 -alkyl,
3) -(Crj-C4)-Alkylen-(C3-C<i2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R11 , Halogen, -C(O)-O-RH , -(C-|-C4)-Alkyl-O-R11 oder -O-(C-|-C4)-Alkyl substituiert ist,3) - (C 1 -C 4 ) -alkylene- (C 3 -C 12 -cycloalkyl, where cycloalkyl is unsubstituted or independently of one another once, twice, three or four times by R 11, Halogen, -C (O) -O-RH, - (C 1 -C 4 ) -alkyl-O-R 11 or -O- (C 1 -C 4 ) -alkyl,
4) -(Co-C4)-Alkylen-C(R11)(R12)-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-RH , -(C<|-C4)-Alkyl-O-R11 oder -O-(Ci-C4)-Aikyl substituiert ist,4) - (Co-C4) -alkylene-C (R11) (R12) - (C 3 -Ci2) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently mono-, di- or trisubstituted by R11, halogen, -C (O ) -O-H, - (C <| -C4) alkyl-O-R11 or substituted -O- (Ci-C4) -alkyl is,
5) -(Co-C4)-Alkylen-Het, wobei unter Het ein 4- bis 15-gliedriges heterocyclisches Ringsystem verstanden wird mit 4 bis 15 Ringatomen, die in ein, zwei oder drei miteinander verbundenen Ringsystemen vorliegen und die ein, zwei, drei oder vier gleiche oder verschiedene Heteroatome aus der Reihe5) - (Co-C4) -alkylene-Het, where Het is a 4- to 15-membered heterocyclic ring system is understood with 4 to 15 ring atoms, which are present in one, two or three interconnected ring systems and the one, two, three or four identical or different heteroatoms from the series
Sauerstoff, Stickstoff oder Schwefel enthalten, wobei Het oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-RH , -(C <|-C4)-Alkyl-O-R11 oder -O-(C-|-C4)-Alkyi substituiert sind, 6) -(Crj-CßJ-Alkylen-Aryl, wobei Aryl oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11, Halogen, -C(O)-O-R11 , -(Cn-C4)-Alkyl-O-R11 oder -O-(C<|-C4)-Alkyl substituiert sind,Oxygen, nitrogen or sulfur, wherein Het or alkylene is unsubstituted or independently of one another mono-, di- or trisubstituted by R11, halogen, -C (O) -O-RH, - (C <| -C4) -alkyl-O-, R11 or -O- (C- | -C4) substituted -Alkyi, 6) - (Cr j -CßJ-alkylene-aryl, wherein aryl or alkylene unsubstituted or substituted independently of one another, di- or trisubstituted by R11, halogen, -C (O) -O-R11, - (Cn-C4) -alkyl-O-R11 or -O- (C <| -C4) -alkyl,
7) -(C0-C4)-Alkylen-C(R11 )(R12)-Aryl, wobei Aryl oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-R11 , -(C0-C4)-Alkyl-O-R11 oder -O-(Ci-C4)-Alkyl substituiert sind,7) - (C 0 -C 4 ) -alkylene-C (R 11) (R 12) -aryl, wherein aryl or alkylene are unsubstituted or independently of one another mono-, di- or trisubstituted by R 11, halogen, -C (O) -O -R11, - (C 0 -C 4) -alkyl-O-R11 or -O- (Ci-C4) alkyl substituted,
8) 1 ,2,3,4-Tetrahydro-naphthalenyl,8) 1, 2,3,4-tetrahydro-naphthalenyl,
9) -(C0-C4)-Alkylen-CH(R11 )-C(O)-NH2,9) - (C 0 -C 4) alkylene-CH (R11) -C (O) -NH 2,
10) -(C0-C4)-Alkylen-CH(R11 J-C(O)-NH-(C1 -C4)-Alkyl, 11) -(C0-C4)-Alkylen-CH(R11)-C(O)-NH-CH(R12)-R13,10) - (C 0 -C 4 ) -alkylene-CH (R 11 JC (O) -NH- (C 1 -C 4 ) -alkyl, 11) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH-CH (R12) -R13,
12) -(Crj-C6)-Alkylen-C(O)-O-R11 , wobei Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch R11 , Halogen, -C(O)-O-R11 , -(C-i^-Alkyl-O-R11 oder -O-(C1-C4)-Alkyl substituiert ist,12) - (Crj-C6) -alkylene-C (O) -O-R11, wherein alkyls are unsubstituted or independently of one another once or twice by R11, halogen, -C (O) -O-R11, - (Ci ^ - Substituted alkyl-O-R11 or -O- (C 1 -C 4 ) -alkyl,
13) -(Cn-C4)-Alkylen-C(R11 )(R12)-C(O)-O-R11 , oder 14) -(Ci-C3)-Fluoralkyl, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom, an das sie gebunden sind, einen mono- oder bicyclischen Ring mit 4 bis 9 Ringatomen bilden, der gesättigt, teilweise gesättigt oder aromatisch ist, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(C-|-C4)-Alkyl, -C(O)-O-R11 , Halogen, -(C-|-C4)-Alkyl-O-R11 oder Phenyl substituiert ist,13) - (Cn-C4) -alkylene-C (R11) (R12) -C (O) -O-R11, or 14) - (Ci-C3) fluoroalkyl, stand, or the two radicals R6 together with the N-atom to which they are attached form a mono- or bicyclic ring having 4 to 9 ring atoms which is saturated, partially saturated or aromatic, the ring being unsubstituted or mono- or disubstituted by - (C 1 -C 4) -alkyl, -C (O) -O-R 11, halogen, - (C 1 -C 4) -alkyl-O-R 11 or phenyl,
R7 für Wasserstoffatom oder -(C<|-C4)-Alkyl steht, R9 für Wasserstoffatom oder -(Ci-C4)-Alkyl steht,R 7 is hydrogen or - (C 1 -C 4) -alkyl, R 9 is hydrogen or - (C 1 -C 4) -alkyl,
R11 und R12 gleich oder verschieden sind und unabhängig voneinander fürR11 and R12 are the same or different and independently of each other
1) Wasserstoffatom, 2) -(C-|-C4)-Alkyl,1) hydrogen atom, 2) - (C 1 -C 4 ) -alkyl,
3) -(Crj-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch Halogen, -OH oder -O-(Ci-C4)-Alkyl substituiert ist,3) - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or independently of one another mono-, di- or trisubstituted by halogen, -OH or -O- (C 1 -C 4) -alkyl,
4) -(Cn-C4)-Alkylen-(C3-C-i2)-Cycloa!kyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R13,4) - (Cn-C4) -alkylene- (C3-C-i2) -cycloalkyl, where cycloalkyl is unsubstituted or independently of one another once, twice, three or four times by R13,
Halogen, -C(O)-O-RI 3, -(C-j-C4)-Alkyl-O-R13, -O-(C<|-C4)-Alkyl oderHalogen, -C (O) -O-RI 3, - (C 1 -C 4) -alkyl-O-R 13, -O- (C 1 -C 4) -alkyl or
-(Crj-C4)-Alkylen-Phenyl substituiert ist,- (Crj-C4) -alkylene-phenyl is substituted,
5) -(C0-C4)-Alkylen-C(O)-N(R13)2 oder5) - (C 0 -C 4 ) -alkylene-C (O) -N (R 13) 2 or
6) -(Cn-C4)-Alkylen-Indolyl, stehen, R13 für 1) Wasserstoffatom,6) - (C 1 -C 4) -alkylene-indolyl, R 13 is 1) hydrogen,
2) -(C1-C4J-AIKyI,2) - (C 1 -C 4 ) -alkyl,
3) -(C0-C4)-Alkylen-C(O)-O-R14,3) - (C 0 -C 4 ) -alkylene-C (O) -O-R 14,
4) -(C0-C4)-Alkylen-C(O)-R14 oder4) - (C 0 -C 4 ) -alkylene-C (O) -R 14 or
5) -(C0-C4)-Alkylen-O-R14 steht, R14 für Wasserstoffatom, -(C<|-C4)-Alkyl, -NH2 oder -OH, steht und5) - (C 0 -C 4) -alkylene-O-R14, R14 is hydrogen atom, - (C <| -C4) alkyl, -NH 2 or -OH, and is
R15 für Wasserstoffatom, -(C-|-C4)-Alkyl, -0-CF3, -NH2, -OH, -CF3 oder Halogen steht.R 15 is hydrogen, - (C 1 -C 4 ) alkyl, -O-CF 3 , -NH 2 , -OH, -CF 3 or halogen.
Die Erfindung betrifft auch die Verbindung der Formel I, wobei X für -C(O)- steht, R1 für 1) Wasserstoffatom oder 2) -(C-|-C4)-Alkyl, steht,The invention also relates to the compound of formula I wherein X is -C (O) -, R 1 represents 1) hydrogen or 2) - (C 1 -C 4) -alkyl,
R2 für 1) -(C -1-Ce)-AIkYIeP-NH2,R2 for 1) - (C-1-Ce) -AlkYIeP-NH 2 ,
2) -(C1-C4)-Alkylen-Pyridyl-NH2, 3) -(C-|-C4)-Alkylen-Piperidinyl-NH2,2) - (C 1 -C 4) -alkylene-pyridyl-NH 2 , 3) - (C 1 -C 4) -alkylene-piperidinyl-NH 2 ,
4) -(C-|-C6)-Alkylen-NH-C(=NH)-NH2,4) - (C 1 -C 6) -alkylene-NH-C (= NH) -NH 2,
5) -(C0-C4)-Alkylen-(C3-C6)-Cycloalkyl-NH2,5) - (C 0 -C 4) -alkylene- (C 3 -C 6) -cycloalkyl-NH 2 ,
6) -(C-i-C6)-Alkylen-NH-C(=NH)-(Ci-C4)-Alkyl,6) - (C 1 -C 6 ) -alkylene-NH-C (NHNH) - (C 1 -C 4) -alkyl,
7) -(C1-C4)-Alkylen-O-NH-C(=NH)-NH2j 8) -(C1-C6)-Alkylen-NH-C(O)-O-(C1-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist,7) - (C 1 -C 4 ) -alkylene-O-NH-C (= NH) -NH 2j 8) - (C 1 -C 6) -alkylene-NH-C (O) -O- (C 1 - C 4) -alkylene-phenyl, where phenyl is unsubstituted or substituted by -NH 2 or substituted by -NH 2 and mono-, di- or trisubstituted by R 15,
9) -(Ci-C4)-Alkylen-NH-C(O)-(Ci-C6)-Alkyl,9) - (C 1 -C 4) -alkylene-NH-C (O) - (C 1 -C 6) -alkyl,
10) -(Ci-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist,10) - (Ci-C4) alkylene-phenyl, where phenyl is unsubstituted or substituted by -NH 2 or -NH 2, and mono-, di- or trisubstituted by R15,
11) -(C1-C4)-Alkylen-SO2-(C1-C4)-Alkylen-NH2, oder11) - (C 1 -C 4 ) -alkylene-SO 2 - (C 1 -C 4 ) -alkylene-NH 2 , or
12) -(Ci-C4)-Alkylen-S-(C-|-C4)-Alkylen-NH2, steht, R3 für 1) -(C !-C4J-AIkYl, 2) -(C1-C4)-Alkylen-(C3-C6)-Cycloalkyl,12) - (C 1 -C 4 ) -alkylene-S- (C 1 -C 4 ) -alkylene-NH 2, R 3 is 1) - (C 1 -C 4 -alkyl-, 2) - (C 1 -C4) -alkylene- (C 3 -C 6 ) -cycloalkyl,
3) -(Ci-C4)-Alkylen-Phenyl, wobei Phenyl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,3) - (C 1 -C 4) -alkylene-phenyl, where phenyl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15,
4) -(C1-C6)-Alkylen-NH-C(O)-O-(Ci-C4)-Alkylen-Phenyl, wobei Phenyl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist, 5) Wasserstoffatom steht,4) - (C 1 -C 6 ) -alkylene-NH-C (O) -O- (C 1 -C 4 ) -alkylene-phenyl, where phenyl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15, 5 ) Is hydrogen,
R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander fürR4 is -N (R6) 2 , wherein R6 are the same or different and independently of one another
1) Wasserstoffatom,1) hydrogen atom,
2) -(C1-C4)-Alkyl, 3) -(Co-C4)-Alkylen-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adaman- tanyl, 1 ,7,7-Trimethyl-bicyclo[3.1.1]heptanyl, Decahydro-naphthalenyl, Tetrahydronaphthalenyl, Octahydro-4,7-methano-indenyl oder Bicyclo[2.2.1]- heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach substituiert ist durch -(Ci-C4)-Alkyl,2) - (C 1 -C 4 ) -alkyl, 3) - (Co-C4) -alkylene- (C3-C12) -cycloalkyl, where cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, 1, 7,7-trimethyl-bicyclo [3.1. 1] heptanyl, decahydro-naphthalenyl, tetrahydronaphthalenyl, octahydro-4,7-methanoindenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently of one another mono-, di-, tri- or tetra-substituted by - ( Ci-C4) alkyl,
-C(O)-O-RH oder -(C-j-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch Halogen substituiert ist,-C (O) -O-RH or - (C-j-C4) -alkylene-phenyl wherein phenyl is unsubstituted or substituted by halogen,
4) -(C0-C4)-Alkylen-C(R11 )(R12)-(C3-C-| 2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl,4) - (C 0 -C 4) -alkylene-C (R 11) (R 12) - (C 3 -C- 2 ) -cycloalkyl, where cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl,
Cyclopropyl, Adamantanyl, 1 ,7,7-Trimethyl-bicyclo[3.1.1]heptanyl, Decahydro- naphthalenyl, Tetrahydronaphthalenyl, Octahydro-4,7-methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach substituiert ist durch -(C-|-C4)-Alkyl, -C(O)-O-R11 oder -(Ci-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch Halogen substituiert ist,Cyclopropyl, adamantanyl, 1,7,7-trimethyl-bicyclo [3.1.1] heptanyl, decahydronaphthalenyl, tetrahydronaphthalenyl, octahydro-4,7-methanoindenyl or bicyclo [2.2.1] heptanyl, and wherein cycloalkyl is unsubstituted or independent of one another is mono-, di-, tri- or tetra-substituted by - (C 1 -C 4) -alkyl, -C (O) -O-R 11 or - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or substituted by Halogen is substituted,
5) -(Co-C4)-Alkylen-Het, wobei Het ausgewählt ist aus der Gruppe Acridinyl,5) - (Co-C4) -alkylene-Het, wherein Het is selected from the group acridinyl,
Azepinyl, Azetidinyl, Aziridinyl, Benzimidazalinyl, Benzimidazolyl, Benzo[1 ,3]dioxolyl, Benzofuranyl, Benzothiofuranyl, Benzothiophenyl, Benzoxazolyl, Benzthiazolyl, Benztriazolyl, Benztetrazolyl, Benzisoxazolyl,Azepinyl, azetidinyl, aziridinyl, benzimidazalinyl, benzimidazolyl, benzo [1,3] dioxolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,
Benzisothiazolyl, Carbazolyl, 4aH-Carbazolyl, Carbolinyl, Chinazolinyl, Chinolinyl, 4H-Chinolizinyl, Chinoxalinyl, Chinuclidinyl, Chromanyl, Chromenyl, Cinnolinyl, Deca-hydrochinolinyl, Dibenzofuranyl, Dibenzothiophenyl, Dihydrofuran[2,3-b]-tetrahydrofuranyl, Dihydrofuranyl, Dioxolyl, Dioxanyl, 2H, 6H-1 ,5,2-Dithiazinyl, Furanyl, Furazanyl, Imidazolidinyl, Imidazolinyl, Imidazolyl,Benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dibenzofuranyl, dibenzothiophenyl, dihydrofuran [2,3-b] tetrahydrofuranyl, dihydrofuranyl, dioxolyl , Dioxanyl, 2H, 6H-1, 5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,
1H-lndazolyl, Indolinyl, Indolizinyl, Indolyl, 3H-lndolyl, Isobenzofuranyl, Isochromanyl, Isoindazolyl, Isoindolinyl, Isoindolyl, Isochinolinyl (Benzimidazolyl), Isothiazolidinyl, 2-lsothiazolinyl, Isothiazolyl, Isoxazolyl, Isoxazolidinyl, 2-lsoxazolinyl, Morpholinyl, Naphthyridinyl, Octahydroisochinolinyl, Oxadiazolyl, 1 ,2,3-Oxadiazolyl, 1 ,2,4-Oxadiazolyl, 1 ,2,5-1H-indazinyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolidinyl, 2-isothiazolinyl, isothiazolyl, isoxazolyl, isoxazolidinyl, 2-isoxazolinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl , Oxadiazolyl, 1, 2,3-oxadiazolyl, 1, 2,4-oxadiazolyl, 1, 2,5-
Oxadiazolyl, 1,3,4-Oxadiazolyl, Oxazolidinyl, Oxazolyl, Oxazolidinyl, Oxothiolanyl, Pyrimidinyl, Phenanthridinyl, Phenanthrolinyl, Phenazinyl, Phenothiazinyl, Phenoxathiinyl, Phenoxazinyl, Phthalazinyl, Piperazinyl, Piperidinyl, Pteridinyl, Purynyl, Pyranyl, Pyrazinyl, Pyroazolidinyl, Pyrazolinyl, Pyrazolyl, Pyridazinyl, Pryidooxazolyl, Pyridoimidazolyl, Pyridothiazolyl, Pyridothiophenyl, Pyridinyl, Pyridyl, Pyrimidinyl, Pyrrolidinyl, Pyrrolinyl, 2H-Oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, Oxothiolanyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridothiophenyl, pyridinyl, pyridyl, Pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-
Pyrrolyl, Pyrrolyl, Tetrahydrofuranyl, Tetrahydroisochinolinyl, Tetrahydrochinolinyl, Tetrahydropyridinyl, 6H-1 ,2,5-Thiadazinyl, 1 ,2,3- Thiadiazolyl, 1 ,2,4-Thiadiazolyl, 1 ,2,5-Thiadiazolyl, 1 ,3,4-Thiadiazolyl, Thianthrenyl, Thiazolyl, Thienyl, Thienoimidazolyl, Thienooxazolyl, Thienopyridin, Thienothiazolyl, Thiomorpholinyl, Thiophenyl, Triazinyl, 1 ,2,3-Pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl, 6H-1, 2,5-thiadazinyl, 1, 2,3-thiadiazolyl, 1, 2,4-thiadiazolyl, 1, 2,5-thiadiazolyl, 1, 3, 4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienoimidazolyl, thienooxazolyl, thienopyridine, thienothiazolyl, thiomorpholinyl, thiophenyl, triazinyl, 1, 2,3-
Triazolyl, 1 ,2,3-Triazolyl, 1 ,2,4-Triazolyl, 1,2,5-Triazolyl, 1,3,4-Triazolyl und Xanthenyl, wobei Het oder Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch -(C-j-C^-Alkyl substituiert istTriazolyl, 1, 2,3-triazolyl, 1, 2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl, wherein Het or alkylene is unsubstituted or independently of one another or by - (CjC ^ alkyl substituted
6) -(C-j-CßJ-Alkylen-Phenyl, wobei Phenyl oder Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Halogen, Phenyl,6) - (C 1 -C 6) -alkylene-phenyl, where phenyl or alkylene is unsubstituted or independently of one another by halogen, phenyl,
-C(O)-O-RH , -(Ci-C4)-Alkyl-O-R11 , -O-(C-|-C4)-Alkyl oder -(C-|-C4)-A!kyl substituiert sind,-C (O) -O-RH, - (C 1 -C 4 ) -alkyl-O-R 11, -O- (C 1 -C 4 ) -alkyl or - (C 1 -C 4 ) -alkyl; are,
7) -(Cn-C4)-Alkylen-C(R11 )(R12)-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch Phenyl oder Fluor substituiert ist,7) - (Cn-C4) -alkylene-C (R11) (R12) -phenyl, where phenyl is unsubstituted or independently of one another mono-, di- or trisubstituted by phenyl or fluorine,
8) 1 ,2,3,4-Tetrahydro-naphthalenyl,8) 1, 2,3,4-tetrahydro-naphthalenyl,
9) -(C0-C4)-Alkylen-CH(R11)-C(O)-NH2,9) - (C 0 -C 4) -alkylene-CH (R 11) -C (O) -NH 2,
10) -(C0-C4)-Alkylen-CH(R11)-C(O)-NH-(Ci-C4)-Alkyl,10) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH- (C 1 -C 4 ) -alkyl,
11) -(C0-C4)-Alkylen-CH(R11)-C(O)-NH-CH(R12)-R13, 12) -(C«|-C6)-Alkylen-C(O)-O-R11 , wobei Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Halogen, Phenyl, -C(O)-O-R11 , -(C-|-C4)-Alkyl-O-R11 , -O-(Ci-C4)-Alkyl oder -(C<|-C4)-Alkyl substituiert ist,11) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH-CH (R 12) -R 13, 12) - (C 1 -C 6) -alkylene-C (O) - O-R11, in which alkyls are unsubstituted or independently of one another by halogen, phenyl, -C (O) -O-R11, - (C 1 -C 4) -alkyl-O-R 11, -O- (C 1 -C 4) C 4 ) -alkyl or - (C 1-C4) -alkyl is substituted,
13) -(C0-C4)-Alkylen-C(R11)(R12)-C(O)-O-R11 , oder 14) -(C-|-C3)-Fluoralkyl, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom an das sie gebunden sind einen Mono- oder Bicyclischen Ring bilden ausgewählt aus der Gruppe Pyrrolidin, Piperidin, 2-Aza-bicyclo[3.2.2]nonan und 7-Aza-bicyclo[2.2.1]hep-tan, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(Ci-C4)-Alkyl, - C(O)-O-R11 , -(C-|-C4)-Alkyl-O-R11 oder Phenyl substituiert ist,13) - (C 0 -C 4) -alkylene-C (R11) (R12) -C (O) -O-R11, or 14) - (C- | -C3) -fluoroalkyl, stand, or the two radicals R6 together with the N-atom to which they are attached form a mono- or bicyclic ring selected from the group consisting of pyrrolidine, piperidine, 2-azabicyclo [3.2.2] nonane and 7-azabicyclo [2.2 .1] hep-tan, where the ring is unsubstituted or mono- or disubstituted by - (C 1 -C 4) -alkyl, - C (O) -O-R 11, - (C 1 -C 4) -alkyl-O-R 11 or phenyl is substituted,
R7 für Wasserstoffatom oder -(C-|-C4)-Alkyl steht, R9 für Wasserstoffatom oder -(C-|-C4)-Alkyl steht,R 7 is hydrogen or - (C 1 -C 4) -alkyl, R 9 is hydrogen or - (C 1 -C 4) -alkyl,
R11 und R12 gleich oder verschieden sind und unabhängig voneinander fürR11 and R12 are the same or different and independently of each other
1 ) Wasserstoffatom , 2) -(C-|-C4)-Alkyl,1) hydrogen atom, 2) - (C 1 -C 4 ) -alkyl,
3) -(Crj-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch -OH, Halogen oder -O-(C-|-C4)-Alkyl substituiert ist,3) - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or independently of one another mono-, di- or trisubstituted by -OH, halogen or -O- (C 1 -C 4) -alkyl,
4) -(Co-C4)-Alkylen-(C3-C-|2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyi, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adamantanyl,4) - (Co-C4) -alkylene- (C3-C- | 2) -cycloalkyl, where cycloalkyl is selected from the group consisting of cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl,
Bicyclo[3.1.1]heptanyl, Decahydro-naphthalenyl, Octahydro-4,7-methano- indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch -(C-|-C4)-Alkyl, -Bicyclo [3.1.1] heptanyl, decahydro-naphthalenyl, octahydro-4,7-methanoindenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently of one, two, three or four times by - (C - | -C4) -alkyl,
C(O)-O-RI 3 oder Phenyl substituiert ist, oder 5) -(Co-C4)-Alkylen-Indolyl, stehen,C (O) -O-RI 3 or phenyl, or 5) - (Co-C4) -alkylene-indolyl,
R13 für 1) Wasserstoffatom,R 13 is 1) hydrogen,
2) -(C1-C4J-AIKyI,2) - (C 1 -C 4 ) -alkyl,
3) -(Co-C4)-Alkylen-C(O)-O-R14,3) - (Co-C4) -alkylene-C (O) -O-R14,
4) -(Co-C4)-Alkylen-C(O)-R14 oder 5) -(Cn-C4)-Alkylen-O-R14 steht,4) - (Co-C 4) -alkylene-C (O) -R 14 or 5) - (Cn-C4) -alkylene-O-R14,
R14 für Wasserstoffatom, -(C-|-C4)-Alkyl, -NH2 oder -OH steht und R15 für Wasserstoffatom, -(Ci-C4J-AIKyI, -0-CF3, -NH2, -OH, -CF3 oder Halogen steht.R 14 is hydrogen, - (C 1 -C 4) -alkyl, -NH 2 or -OH and R 15 is hydrogen, - (C 1 -C 4 -alkyl, -O-CF 3 , -NH 2 , -OH, -CF3 or halogen.
Die Erfindung betrifft auch die Verbindung der Formel I, wobei X für -C(O)- steht,The invention also relates to the compound of formula I wherein X is -C (O) -,
R1 für 1) Wasserstoffatom oderR1 for 1) hydrogen atom or
2) -(C<|-C4)-Alkyl, steht,2) - (C <| -C4) alkyl, is,
R2 für 1) -(Ci-C6)-Alkylen-NH2, 2) -(C1-C4)-Alkylen-Pyridyl-NH2) R 2 for 1) - (C 1 -C 6 ) -alkylene-NH 2 , 2) - (C 1 -C 4) -alkylene-pyridyl-NH 2)
3) -(Ci-C4)-Alkylen-Piperidinyl-NH2,3) - (C 1 -C 4) -alkylene-piperidinyl-NH 2,
4) -(C1-C4)-Alkylen-NH-C(=NH)-NH2,4) - (C 1 -C 4 ) -alkylene-NH-C (= NH) -NH 2,
5) -(C1-C6)-Alkylen-NH-C(=NH)-(C1-C4)-Alkyl,5) - (C 1 -C 6 ) -alkylene-NH-C (= NH) - (C 1 -C 4 ) -alkyl,
6) -(Ci-C4)-Alkylen-(C3-C6)-Cycloalkyl-NH2, 7) -(C1-C4)-Alkylen-O-NH-C(=NH)-NH2i 6) - (Ci-C4) alkylene- (C3-C6) cycloalkyl-NH 2, 7) - (C 1 -C 4) -alkylene-O-NH-C (= NH) -NH 2i
8) -(C1-C6)-Alkylen-NH-C(O)-O-(C1-C4)-Alkylen-Phenyl,8) - (C 1 -C 6 ) -alkylene-NH-C (O) -O- (C 1 -C 4 ) -alkylene-phenyl,
9) -(C^C^-Alkylen-NH-CCOMC-i-CeJ-Alkyl,9) - (C 1 -C 4) -alkylene-NH-CCOMC-i-CeJ-alkyl,
10) -(C1-C4)-Alkylen-Phenyl-NH2,10) - (C 1 -C 4 ) -alkylene-phenyl-NH 2 ,
11) -(Ci-C2)-Alkylen-SO2-(C1-C4)-Alkylen-NH2, oder 12) -(C1 -C2)-Alkylen-S-(Ci-C4)-Alkylen-NH2, steht,11) - (C 1 -C 2 ) -alkylene-SO 2 - (C 1 -C 4 ) -alkylene-NH 2 , or 12) - (C 1 -C 2 ) -alkylene-S- (C 1 -C 4 ) Alkylene-NH 2 ,
R3 für 1) -(C^C^-Alkyl,R 3 is 1) - (C 1 -C 4) -alkyl,
2) -(C-i -C4)-Alkylen-(C3-C6)-Cycloalkyl,2) - (C 1 -C 4 ) -alkylene- (C 3 -C 6 ) -cycloalkyl,
3) -(C-|-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch -OH substituiert ist, 4) -(C1 -Ce)-AIkVIeIi-NH-C(O)-O-(C1 -C4)-Alkylen-Phenyl,3) - (C 1 -C 4 ) -alkylene-phenyl, where phenyl is unsubstituted or substituted by -OH, 4) - (C 1 -C 6) -AlkVl- 1 -NH-C (O) -O- (C 1 -C 4 ) -alkylene-phenyl,
5) Wasserstoffatom steht, R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander für 1 ) Wasserstoffatom , 2) -(C^CeJ-Alkyl,5) is hydrogen, R 4 is -N (R 6) 2 , where R 6 are identical or different and independently of one another represent 1) hydrogen, 2) - (C 1 -C 6 -alkyl,
3) -(Cn-C4)-Alkylen-(C3-C8)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclopropyl, Adamantanyl, 1 ,7,7- Trimethyl-bicyclo[3.1.1]heptanyl, Decahydro-naphthalenyl, Octahydro-4,7- methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch -(C-|-C4)-Alkyl oder Phenyl substituiert ist,3) - (Cn-C4) -alkylene- (C3-C8) -cycloalkyl, wherein cycloalkyl is selected from the group consisting cyclohexyl, cyclopentyl, cyclopropyl, adamantanyl, 1, 7,7-trimethyl-bicyclo [3.1.1] heptanyl , Decahydro-naphthalenyl, octahydro-4,7-methano-indenyl or bicyclo [2.2.1] heptanyl and wherein cycloalkyl is unsubstituted or independently of one another monosubstituted, disubstituted or trisubstituted by - (C 1 -C 4) -alkyl or phenyl,
4) -C(R11 )(R12)-Adamantanyl,4) -C (R11) (R12) adamantanyl,
5) -CH(R11)-C(O)-NH-CH(R12)-R13, 6) -(C()-C4)-Alkylen-Het, wobei Het ausgewählt ist aus der Gruppe5) -CH (R11) -C (O) -NH-CH (R12) -R13, 6) - (C () -C4) -alkylene-Het, wherein Het is selected from the group
Benzimidazolyl, Isoxazolyl, Piperidinyl, Pyridyl, Pyrrolidinyl, Thiophenyl und Benzo[1 ,3]dioxolyl,Benzimidazolyl, isoxazolyl, piperidinyl, pyridyl, pyrrolidinyl, thiophenyl and benzo [1,3] dioxolyl,
7) 1 ,2,3,4-Tetrahydro-naphthalenyl,7) 1, 2,3,4-tetrahydro-naphthalenyl,
8) -(Cn-C4)-Alkylen-C(R11)(R12)-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch Phenyl oder Fluor substituiert ist,8) - (Cn-C4) -alkylene-C (R11) (R12) -phenyl, where phenyl is unsubstituted or independently of one another mono-, di- or trisubstituted by phenyl or fluorine,
9) -CH(RH)-C(O)-NH2,9) -CH (RH) -C (O) -NH 2 ,
10) -CH(RI 1)-C(O)-NH-CH(R12)-CH2-OH,10) -CH (RI 1) -C (O) -NH-CH (R 12) -CH 2 -OH,
11) -(C-j-C6)-Alkylen-Phenyl, wobei Phenyl oder Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Chlor, Fluor,11) - (C 1 -C 6) -alkylene-phenyl, where phenyl or alkylene is unsubstituted or independently of one another by chlorine, fluorine,
-C(O)-O-RH, -(C-|-C4)-Alkyl-O-R11 , -O-(C-i-C4)-Alkyl, Phenyl oder-C (O) -O-RH, - (C 1 -C 4) -alkyl-O-R 11, -O- (C 1 -C 4 ) -alkyl, phenyl or
-(C-|-C4)-Alkyl substituiert sind,- (C 1 -C 4) -alkyl are substituted,
12) -CH(RI 1)-C(O)-NH-(C<|-C4)-Alkyl,12) -CH (RI 1) -C (O) -NH- (C 1 -C 4 ) -alkyl,
13) -(C0-C4)-Alkylen-C(R11)(R12)-Bicyclo[3.1.1]heptanyl, wobei Bicyclo[3.1.1]heptanyl unsubstituiert oder ein- bis vierfach durch13) - (C 0 -C 4 ) -alkylene-C (R 11) (R 12) -bicyclo [3.1.1] heptanyl, where bicyclo [3.1.1] heptanyl is unsubstituted or mono- to quadruple
-(Ci-C4)-Alkyl substituiert ist,- (C 1 -C 4) -alkyl is substituted,
14) -(C<|-C6)-Alkylen-C(O)-O-R11 , wobei Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Chlor, Fluor, -C(O)-O-RH , -(C<|-C4)-Alkyl-O-R11 , -O-(Ci-C4)-Alkyl, Phenyl oder -(C-j-C4)-Alkyl substituiert ist,14) - (C <| - C6) -alkylene-C (O) -O-R11, wherein alkylene is unsubstituted or independently of one another by chlorine, fluorine, -C (O) -O-RH, - (C <C 1 -C 4) -alkyl-O-R 11, -O- (C 1 -C 4 ) -alkyl, phenyl or - (C 1 -C 4 ) -alkyl,
15) -(C0-C4)-Alkylen-C(R11 )(R12)-C(O)-O-R11 , oder15) - (C 0 -C 4) -alkylene-C (R 11) (R 12) -C (O) -O-R 11, or
16) -CH2-CF2-CF3, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom an das sie gebunden sind einen Mono- oder Bicyclischen Ring bilden, ausgewählt aus der Gruppe Pyrrolidine, 2-aza-bicyclo[3.2.2]nonan und 7-aza-bicyclo[2.2.1]heptan, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(C-j-C^-Alkyl, -C(O)-O-R11 , -(C-|-C4)-Alkyl-O-R11 oder Phenyl substituiert ist,16) -CH2-CF2-CF3, or the two radicals R6 together with the N-atom to which they are attached form a mono- or bicyclic ring selected from the group consisting of pyrrolidines, 2-aza-bicyclo [3.2.2 ] nonane and 7-aza-bicyclo [2.2.1] heptane, where the ring is unsubstituted or mono- or disubstituted by - (C 1 -C 4 -alkyl, -C (O) -O-R 11, - (C 1 -C 4) -alkyl-O-R 11 or phenyl,
R7 für Wasserstoffatom oder -(C-|-C4)-Alkyl steht,R 7 is hydrogen or - (C 1 -C 4) -alkyl,
R9 für Wasserstoffatom oder -(C-|-C4)-Alkyl steht, R11 und R12 gleich oder verschieden sind und unabhängig voneinander fürR 9 is hydrogen or - (C 1 -C 4) -alkyl, R 11 and R 12 are the same or different and are each independently
1 ) Wasserstoffatom ,1) hydrogen atom,
2) -(C1-C4J-AIICyI1 2) - (C 1 -C 4 -alkyl ) 1
3) -(Crj-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch -OH, Halogen oder -O-(C 1 -C4)-Alkyl substituiert ist,3) - (Crj-C4) -alkylene-phenyl, wherein phenyl is unsubstituted or substituted independently of one another once, twice or three times by -OH, halogen or -O- (C 1 -C 4) -alkyl,
4) -(Co-C4)-Alkylen-(C3-C-|2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adaman- tanyl, 1 ,7,7-Trimethyl-bicyclo[3.1.1]heptanyl, Decahydro-naphthalenyl, Octahydro-4,7-methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch -(C-|-C4)-Alkyl, -C(O)-O-RI 3 oder Phenyl substituiert ist, oder4) - (Co-C4) -alkylene- (C3-C- | 2) -cycloalkyl, wherein cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, 1, 7,7-trimethyl-bicyclo [3.1.1] heptanyl, decahydro-naphthalenyl, octahydro-4,7-methano-indenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently of one another, one, two, three or four times by C 1 -C 4) -alkyl, -C (O) -O-RI 3 or phenyl, or
5) -(Cfj-C4)-Alkylen-Indolyl, stehen, R13 für 1 ) Wasserstoffatom,5) - (Cfj-C4) -alkylene-indolyl, R13 is 1) hydrogen,
2) -(C1-C4J-AIlCyI. 3) -(Co-C4)-Alkylen-C(0)-0-R14,2) - (C 1 -C 4 J-C AIl yI 3). - (Co-C 4) -alkylene-C (0) -0-R14,
4) -(Cn-C4)-Alkylen-C(O)-R14 oder4) - (Cn-C4) -alkylene-C (O) -R 14 or
5) -(Cn-C4)-Alkylen-O-R14 steht,5) - (Cn-C4) -alkylene-O-R14,
R14 für Wasserstoffatom, -(C1-C4J-AIlCyI1 -NH2 oder -OH steht und R15 für Wasserstoffatom, -(C-|-C4)-Alkyl, -0-CF3, -NH2, -OH, -CF3 oder Halogen steht.R14 is hydrogen atom, - (C 1 -C 4 J-AIlCyI 1 -NH 2 or -OH and R15 represents hydrogen atom, - (C- | -C4) alkyl, -0-CF 3, -NH 2, -OH, -CF3 or halogen.
Unter dem Begriff „(C-i-CßJ-Alkyl" werden Kohlenwasserstoffreste verstanden, derenBy the term "(C-i-CβJ-alkyl" is meant hydrocarbon radicals whose
Kohlenstoffkette geradkettig oder verzweigt ist und 1 bis 6 Kohlenstoffatome enthält, beispielsweise Methyl, Ethyl, Propyl, Iso-Propyl, Butyl, Iso-Butyl, tertiär-Butyl, Pentyl, Iso-Pentyl, Neopentyl, Hexyl, 2,3-Dimethylbutan oder Neohexyl. Unter dem Begriff ,,-(Co-C4)-Alkylen" werden Kohlenwasserstoff reste verstanden, deren Kohlenstoffkette geradkettig oder verzweigt ist und 1 bis 4 Kohlenstoff atome enthält, beispielsweise Methylen, Ethylen, Propylen, Iso-Propylen, Iso-Butylen, Butylen oder tertiär-Butylen. ,,-Crj-Alkylen" ist eine kovalente Bindung. Unter dem Begriff ,,-(CH2)rr. worin n die ganze Zahl Null oder 1 bedeutet" wird für den Fall n gleich 1 der Rest Methylen verstanden und für den Fall das n die ganze Zahl Null bedeutet, hat der Rest die Bedeutung einer kovalenten Bindung. Unter dem Begriff ,,-(C-|-C4)-Alkylen" werden Kohlenwasserstoffreste verstanden, deren Kohlenstoffkette geradkettig oder verzweigt ist und 1 bis 4 Kohlenstoffatome enthält, beispielsweise Methylen (-CH2-), Ethylen (-CH2-CH2-), Propylen (-CH2-CH2- CH2-), Iso-Propylen, Iso-Butylen, Butylen oder tertiär-Butylen.Carbon chain is straight-chain or branched and contains 1 to 6 carbon atoms, for example methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, pentyl, iso-pentyl, neo-pentyl, hexyl, 2,3-dimethylbutane or neohexyl , The term "- (Co-C4) -alkylene" means hydrocarbon radicals whose carbon chain is straight-chain or branched and contains 1 to 4 carbon atoms, for example methylene, ethylene, propylene, iso-propylene, iso-butylene, butylene or tertiary-butylene, "- Cr j -alkylene" is a covalent bond. By the term ,, - (CH 2) rr. where n is the integer zero or 1 "is the radical methylene for the case n is equal to 1 and in the case where n is the integer zero, the radical has the meaning of a covalent bond --C-C4) -alkylene "are hydrocarbon radicals whose carbon chain is straight-chain or branched and contains 1 to 4 carbon atoms, for example methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -), propylene (-CH 2 -CH 2 -CH 2 -), iso-propylene, iso-butylene, butylene or tertiary-butylene.
Unter dem Begriff ,,-(CH2)n-. worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet" werden Reste wie Methylen, Ethylen oder Propylen verstanden. Für den Fall das n die ganze Zahl Null bedeutet, hat der Rest die Bedeutung einer kovalenten Bindung. Unter dem Begriff „(C3-C-12)-Cycloalkyl" werden Reste verstanden wie Verbindungen, die sich von 3- bis 12-gliedrige Mono-, Bi- oder Tricyclen oder überbrücken Cyclen wie den Monocyclen Cyclopropan, Cyclobutan, Cyclopentan, Cyclohexan, Cycloheptan oder Cyclooctan herleiten, die sich von den Bicyclen Bicyclo[4.2.0]octan, Octahydro- inden, Decahydro-naphthalen, Decahydro-azulen, Decahydro-benzocyclohepten oder Dodecahydro-heptalen, oder von Tricyclen wie Adamantan herleiten oder von den überbrücken Cyclen wie Spiro[2.5]octan, Spiro[3.4]octan, Spiro[3.5]nonan, Bicyclo[3.1.1]heptan, Bicyclo[2.2.1]heptan, Bicyclo[2.2.2]octan oder Octahydro-4,7- methan-inden herleiten. Unter dem Begriff „R6 zusammen mit dem N-Atom an das sie gebunden sind einen Mono- oder Bicyclischen Ring mit 4 bis 9 Ringatomen bilden" werden Reste verstanden wie Verbindungen, die sich von 4- bis 8-gliedrige Monocyclen ableiten die gestättigt oder ganz oder teilweise aromatisch sein können zum Beispiel Azetidin, Dihydroazet, Azet, Diazetidin, Diazet, Pyrrolidin, Dihydropyrrol, Pyrrol, Imidazolidin, Dihydroimidazol, Imidazol, Pyrazolin, Pyrazolidin, Piperidin, Dihydropyridin, Tetrahydropyridin, Pyridin, Piperazin, Dihydropyrazin, Pyrazin, Pyridazin, Pyrimidin, Oxazin, Azepan, Tetrahydroazepin, Azepin, Azocan, Dihydroazocin, Hexohydroazocin oder Azocin oder bicyclische Ringe wie 2-aza-bicyclo[3.2.2]nonan oder, 7-aza- bicyclo[2.2.1 ]heptan.By the term ,, - (CH2) n-. where n is the integer zero, 1, 2 or 3, "radicals such as methylene, ethylene or propylene are understood, and in the case where n is zero, the radical has the meaning of a covalent bond -C-12) -Cycloalkyl "radicals are understood as compounds derived from 3- to 12-membered mono-, bi- or tricyclene or bridging cycles such as the monocycles cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane or cyclooctane, the derived from the bicyclic bicyclo [4.2.0] octane, octahydroindene, decahydro-naphthalene, decahydro-azulene, decahydrobenzocycloheptene or dodecahydroheptalen, or from tricyclic compounds such as adamantane or from the bridged cycles such as spiro [2.5] octane, Spiro [3.4] octane, spiro [3.5] nonane, bicyclo [3.1.1] heptane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane or octahydro-4,7-methane-indene. The term "R6 together with the N-atom to which they are attached form a mono- or bicyclic ring having 4 to 9 ring atoms" is understood to mean radicals such as compounds derived from 4- to 8-membered monocycles which are saturated or entirely or partially aromatic, for example, azetidine, dihydroacetate, acetone, diazetidine, diacetate, pyrrolidine, dihydropyrrole, pyrrole, imidazolidine, dihydroimidazole, imidazole, pyrazoline, pyrazolidine, piperidine, dihydropyridine, tetrahydropyridine, pyridine, piperazine, dihydropyrazine, pyrazine, pyridazine, pyrimidine , Oxazine, azepane, tetrahydroazepine, azepine, azocane, dihydroazocine, hexohydroazocine or azocine or bicyclic rings such as 2-aza-bicyclo [3.2.2] nonane or, 7-azabicyclo [2.2.1] heptane.
Unter dem Begriff ,,-(Cg-C 14)-Ary I" werden aromatische Kohlenstoffreste verstanden mit β bis 14 Kohlenstoffatomen im Ring. -(Cg-Ci 4)-Arylreste sind beispielsweise Phenyl, Naphthyl, zum Beispiel 1-Naphthyl, 2-Naphthyl, 1,2,3,4-Tetrahydro- naphthalenyl, Anthryl oder Fluorenyl. Naphthylreste und insbesondere Phenylreste sind bevorzugte Arylreste.The term "- (Cg-C 14) -Ary I" is understood to mean aromatic carbon radicals having from β to 14 carbon atoms in the ring - (C 9 -C 14) -Aryl radicals are, for example, phenyl, naphthyl, for example 1-naphthyl, 2 Naphthyl, 1,2,3,4-tetrahydronaphthalenyl, anthryl or fluorenyl. Naphthyl radicals and in particular phenyl radicals are preferred aryl radicals.
Unter dem Begriff „4- bis 15-gliedriger Het-Ring" oder „Het" werden Ringsysteme verstanden mit 4 bis 15 Kohlenstoffatomen, die in ein, zwei oder drei miteinander verbundenen Ringsystemen vorliegen und die ein, zwei, drei oder vier gleiche oder verschiedene Heteroatome aus der Reihe Sauerstoff, Stickstoff oder Schwefel enthalten. Beispiele für diese Ringsysteme sind die Reste Acridinyl, Azepinyl, Azetidinyi, Aziridinyl, Benzimidazalinyl, Benzimidazolyl, Benzo[1 ,3]dioxol, Benzofuranyl, Benzothiofuranyl, Benzothiophenyl, Benzoxazolyl, Benzthiazolyl, Benztriazolyl, Benztetrazolyl, Benzisoxazolyl, Benzisothiazolyl, Carbazolyl, 4aH- Carbazolyl, Carbolinyl, Chinazolinyl, Chinolinyl, 4H-Chinolizinyl, Chinoxalinyl, Chinuclidinyl, Chromanyl, Chromenyl, Cinnolinyl, Deca-hydrochinolinyl, Dibenzofuranyl, Dibenzothiophenyl, Dihydrofuran[2,3-b]-tetrahydrofuranyl, Dihydrofuranyl, Dioxolyl, Dioxanyl, 2H, 6H-1 ,5,2-Dithiazinyl, Furanyl, Furazanyl, Imidazolidinyl, Imidazolinyl, Imidazolyl, 1H-lndazolyl, Indolinyl, Indolizinyl, Indolyl, 3H- Indolyl, Isobenzofuranyl, Isochromanyl, Isoindazolyl, Isoindolinyl, Isoindolyl, Isochinolinyl (Benzimidazolyl), Isothiazolidinyl, 2-lsothiazolinyl, Isothiazolyl, Isoxazolyl, Isoxazolidinyl, 2-lsoxazolinyl, Morpholinyl, Naphthyridinyl, Octahydroisochinolinyl, Oxadiazolyl, 1 ,2,3-Oxadiazolyl, 1 ,2,4-Oxadiazolyl, 1 ,2,5-Oxadiazolyl, 1 ,3,4- Oxadiazolyl, Oxazolidinyl, Oxazolyl, Oxazolidinyl, Oxothiolanyl, Pyrimidinyl, Phenanthridinyl, Phenanthrolinyl, Phenazinyl, Phenothiazinyl, Phenoxathiinyl, Phenoxazinyl, Phthalazinyl, Piperazinyl, Piperidinyl, Pteridinyl, Purynyl, Pyranyl, Pyrazinyl, Pyroazolidinyl, Pyrazolinyl, Pyrazolyl, Pyridazinyl, Pryidooxazolyl, Pyridoimidazolyl, Pyridothiazolyl, Pyridothiophenyl, Pyridinyl, Pyridyl, Pyrimidinyl, Pyrrolidinyl, Pyrrolinyl, 2H-Pyrrolyl, Pyrrolyl, Tetrahydrofuranyl, Tetrahydroisochinolinyl, Tetrahydrochinolinyl, Tetrahydropyridinyl, 6H-1 ,2,5-Thiadazinyl, 1 ,2,3-Thiadiazolyl, 1 ,2,4-Thiadiazolyl, 1 ,2,5-Thiadiazolyl, 1 ,3,4-Thiadiazolyl, Thianthrenyl, Thiazolyl, Thienyl, Thienoimidazolyl, Thienooxazolyl, Thienopyridin, Thienothiazolyl, Thiomorpholinyl, Thiophenyl, Triazinyl, 1 ,2,3-Triazolyl, 1 ,2,3-Triazolyl, 1 ,2,4-Triazolyl, 1,2,5-Triazolyl, 1 ,3,4-Triazolyl und Xanthenyl.The term "4- to 15-membered Het ring" or "Het" is understood as meaning ring systems having 4 to 15 carbon atoms which are present in one, two or three interconnected ring systems and which are one, two, three or four identical or different Heteroatoms from the series oxygen, nitrogen or sulfur included. Examples of these ring systems are the radicals acridinyl, azepinyl, azetidinyl, aziridinyl, benzimidazalinyl, benzimidazolyl, benzo [1,3] dioxole, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl , Carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, deca-hydroquinolinyl, dibenzofuranyl, dibenzothiophenyl, dihydrofuran [2,3-b] tetrahydrofuranyl, dihydrofuranyl, dioxolyl, dioxanyl, 2H, 6H- 1,2,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolidinyl, 2 -lsothiazolinyl, isothiazolyl, isoxazolyl, isoxazolidinyl, 2-isoxazolinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1, 2,3-oxadiazolyl, 1, 2,4-oxadiazolyl, 1, 2,5-oxadiazolyl, 1, 3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, oxothiolanyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, Piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl, 6H-1, 2,5-thiadazinyl, 1, 2,3-thiadiazolyl, 1, 2,4-thiadiazolyl, 1, 2,5-thiadiazolyl, 1, 3,4-thiadiazolyl, thianthrenyl, thiazolyl, Thienyl, thienoimidazolyl, thienooxazolyl, thienopyridine, thienothiazolyl, thiomorpholinyl, thiophenyl, triazinyl, 1, 2,3-triazolyl, 1, 2,3-triazolyl, 1, 2,4-triazolyl, 1,2,5-triazolyl, 1, 3,4-triazolyl and xanthenyl.
Bevorzugte Het-Ringe sind die Reste Isoxazolyl, Benzo[1 ,3]dioxol und Thiophenyl. Unter dem Begriff „Halogen" wird Fluor, Chlor, Brom oder Jod verstanden, bevorzugt sind Fluor, Chlor oder Brom, insbesondere Chlor oder Brom.Preferred Het rings are the radicals isoxazolyl, benzo [1, 3] dioxole and thiophenyl. The term "halogen" is understood to mean fluorine, chlorine, bromine or iodine, preference is given to fluorine, chlorine or bromine, in particular chlorine or bromine.
Unter dem Begriff „Aminosäure" werden Verbindungen wie natürlich vorkommende α- Aminosäuren Glycin, Alanin, Valin, Leucin, Isoleucin, Phenylalanin, Tyrosin, Tryptophan, Serin, Threonin, Cystein, Methionin, Asparagin, Glutamin, Lysin, Histidin, Arginin, Glutaminsäure und Asparaginsäure verstanden. Insbesondere bevorzugt sind Histidin, Tryptophan, Serin, Threonin, Cystein, Methionin, Asparagin, Glutamin, Lysin, Arginin, Glutaminsäure und Asparaginsäure. Ferner gehören dazu auch nicht natürlich vorkommenden Aminosäuren wie 2-Aminoadipinsäure, 2-Aminobuttersäure, 2- Aminoisobuttersäure , 2,3-Diamino-propionsäure, 2,4-Diaminobuttersäure, 1 ,2,3,4- Tetra-hydroisochinolin-1 -carbonsäure, 1,2,3,4-Tetrahydroisochinolin-3-carbonsäure, 2- Amino-pimelinsäure, Phenylglycin, 3-(2-Thienyl)-alanin, 3-(3-Thienyl)-alanin, Sarkosin, 2-(2-Thienyl)-glycin, 2-Amino-heptansäure, Pipecolinsäure, Hydroxylysin, N- Methylisoleucin, 6-N-Methyllysin, N-Methylvalin, Norvalin, Norleudn, Ornithin, allo- Isoleucin, 4-Hydroxy-prolin, allo-Hydroxylysin, allo-Threonin, 3-Hydroxyprolin, 3-(2- Naphtyl)-alanin, 3-(1-Naphtylalanin), Homophenylalanin, Homocystein, 2-Amino-3- phenylaminoethyl-propion-säure, Homocysteinsäure, Homotryptophan, Cysteinsäure, 3-(2-Pyridyl)-alanin, 3-(3-Pyridyl)-alanin, 3-(4-Pyridyl)-alanin, Phosphinothricin, A- Fluorphenyl-alanin, 3-Fluor-phenylalanin, 4-Fluorphenylalanin, 3-Fluorphenylalanin, 3- Fluorphenylalanin, 2-Fluorphenylalanin, 4-Chlorphenylalanin, 4-Nitrophenylalanin, A- Aminophenylalanin, Cyclo-hexylalanin, Citrullin, 5-Fluortryptophan, 5-The term "amino acid" includes compounds such as naturally occurring α-amino acids glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid and Particular preference is given to histidine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, arginine, glutamic acid and aspartic acid, as well as non-naturally occurring amino acids such as 2-aminoadipic acid, 2-aminobutyric acid, 2-aminoisobutyric acid , 2,3-diamino-propionic acid, 2,4-diaminobutyric acid, 1, 2,3,4-tetra-hydroisoquinoline-1-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2-amino-pimelic acid , Phenylglycine, 3- (2-thienyl) alanine, 3- (3-thienyl) alanine, sarcosine, 2- (2-thienyl) glycine, 2-amino-heptanoic acid, pipecolic acid, hydroxylysine, N-methylisoleucine, 6 N-methyllysine, N-methylvaline, norvaline, Norleudn, Ornith in, allo-isoleucine, 4-hydroxy-proline, allo-hydroxylysine, allo-threonine, 3-hydroxyproline, 3- (2-naphthyl) -alanine, 3- (1-naphthylalanine), homophenylalanine, homocysteine, 2-amino- 3-phenylaminoethylpropionic acid, homocysteic acid, homotryptophan, cysteic acid, 3- (2-pyridyl) alanine, 3- (3-pyridyl) alanine, 3- (4-pyridyl) alanine, phosphinothricin, A-fluorophenyl alanine, 3-fluoro-phenylalanine, 4-fluorophenylalanine, 3-fluorophenylalanine, 3-fluorophenylalanine, 2-fluorophenylalanine, 4-chlorophenylalanine, 4-nitrophenylalanine, A-aminophenylalanine, cyclohexylalanine, citrulline, 5-fluorotryptophan, 5-
Methoxytryptophan oder 2-Amino-3-phenylamino-propionsäure verstanden. Unter dem Begriff „Peptid-Bindung" werden Strukturen wie
Figure imgf000060_0001
Methoxytryptophan or 2-amino-3-phenylamino-propionic understood. The term "peptide bond" refers to structures such as
Figure imgf000060_0001
verstanden. Unter dem Begriff „Schutzgruppe für die Amino-, Carboxyl- oder für die Hydroxyfunktion" werden Schutzgruppen verstanden wie geeignete Schutzgruppen für Aminofunktionen, beispielweise die t-Butoxycarbonyl-, die Benzyloxycarbonyl- oder die Phtalolylgruppe sowie die Trityl- oder Tosylschutzgruppe, geeignete Schutzgruppen für die Carboxylfunktion sind beispielweise Alkyl-, Aryl- oder Arylalkylester und geeignete Schutzgruppen für die Hydroxyfunktion sind beispielsweise Alkylester, t- Butyl-, Benzyl- oder Tritylgruppen. Schutzgruppen können durch wohlbekannte oder hier beschriebene Techniken eingeführt und entfernt werden (siehe Green, T. W., Wutz, P.G.M., Protective Groups in Organic Synthesis (1991), 2nd Ed., Wϊley- Interscience, oder Kocienski, P., Protecting Groups (1994), Thieme).Understood. The term "protecting group for the amino, carboxyl or for the hydroxyl function" is understood to mean protective groups such as suitable protective groups for amino functions, for example the t-butoxycarbonyl, the benzyloxycarbonyl or the phthalolyl group and the trityl or tosyl protecting group, suitable protective groups for the Carboxyl function are, for example, alkyl, aryl or arylalkyl esters and suitable protecting groups for the hydroxy function are, for example, alkyl esters, t-butyl, benzyl or trityl groups Protecting groups can be introduced and removed by well-known or described techniques (see Green, TW, Wutz, PGM, Protective Groups in Organic Synthesis (1991), 2nd Ed., Wϊley-Interscience, or Kocienski, P., Protecting Groups (1994), Thieme).
Unter dem Begriff ,,-(C-|-C3)-Fluoralkyl" wird ein partiell oder vollständig fluorierterBy the term "- (C 1 -C 3) fluoroalkyl" is meant a partially or fully fluorinated
Alkylrest verstanden, der sich beispielsweise von folgenden Resten ableitet -CF3, -CHF2, -CH2F, -CHF-CF3, -CHF-CHF2, -CHF-CH2F, -CH2-CF3, -CH2-CHF2, -CH2-CH2F, -CF2-CF3, -CF2-CHF2, -CF2-CH2F, -CH2-CHF-CF3, -CH2-CHF-CHF2, -CH2-CHF-CH2F, -CH2-CH2-CF3, -CH2-CH2-CHF2, -CH2-CH2-CH2F, -CH2-CF2-CF3, -CH2-CF2-CHF2, -CH2-CF2-CH2F, -CHF-CHF-CF3, -CHF-CHF-CHF2, -CHF-CHF-CH2F, -CHF-CH2-CF3, -CHF-CH2-CHF2, -CHF-CH2-CH2F, -CHF-CF2-CF3, -CHF-CF2-CHF2, -CHF-CF2-CH2F, -CF2-CHF-CF3, -CF2-CHF-CHF2, -CF2-CHF-CH2F, -CF2-CH2-CF3, -CF2-CH2-CHF2, -CF2-CH2-CH2F, -CF2-CF2-CF3, -CF2-CF2-CHF2 oder -CF2-CF2-CH2F. Unter dem Begriff ,,-SO2-" wird ein Sulfonyl-Rest verstanden. Unter dem Begriff ,,-C(O)-" wird ein Carbonyl-Rest verstanden.Alkyl radical derived, for example, from the following radicals -CF3, -CHF 2 , -CH 2 F, -CHF-CF 3 , -CHF-CHF 2 , -CHF-CH 2 F, -CH 2 -CF 3 , -CH 2 -CHF 2 , -CH 2 -CH 2 F, -CF 2 -CF 3 , -CF 2 -CHF 2 , -CF 2 -CH 2 F, -CH 2 -CHF-CF 3 , -CH 2 -CHF- CHF 2 , -CH 2 -CHF-CH 2 F, -CH 2 -CH 2 -CF 3 , -CH 2 -CH 2 -CHF 2 , -CH 2 -CH 2 -CH 2 F, -CH 2 -CF 2 -CF 3 , -CH 2 -CF 2 -CHF 2 , -CH 2 -CF 2 -CH 2 F, -CHF-CHF-CF 3 , -CHF-CHF-CHF 2 , -CHF-CHF-CH 2 F, -CHF-CH 2 -CF 3 , -CHF-CH 2 -CHF 2 , -CHF-CH 2 -CH 2 F, -CHF-CF 2 -CF 3 , -CHF-CF 2 -CHF 2 , -CHF-CF 2 -CH 2 F, -CF 2 -CHF-CF 3 , -CF 2 -CHF-CHF 2 , -CF 2 -CHF-CH 2 F, -CF 2 -CH 2 -CF 3 , -CF 2 -CH 2 -CHF 2 , -CF 2 -CH 2 -CH 2 F, -CF 2 -CF 2 -CF 3 , -CF 2 -CF 2 -CHF 2 or -CF 2 -CF 2 -CH 2 F. "-SO 2 -" is understood as meaning a sulfonyl radical. The term "- C (O) -" is understood as meaning a carbonyl radical.
Die Erfindung betrifft ferner ein Verfahren zur Herstellung der Verbindung der Formel I1 das dadurch gekennzeichnet, dass man a) eine Verbindung der Formel Il oThe invention further relates to a process for the preparation of the compound of the formula I 1, which comprises reacting a) a compound of the formula II
H J N γA o ^ P G ( l l ) H J N γ A o ^ PG (II)
R 2 wobei R2 und PG die in der Verbindung der Formel I genannten Bedeutungen haben, mit einem Phosgenäquivalent wie Carbonyldiimidazol, Diphosgen, Triphosgen oder Phosgen zu einer Zwischenverbindung der Formel IM umsetzt,R 2 where R 2 and PG have the meanings given in the compound of the formula I, with a phosgene equivalent such as carbonyldiimidazole, diphosgene, triphosgene or phosgene to give an intermediate compound of the formula III,
Figure imgf000062_0001
wobei R2 und PG die in der Verbindung der Formel I genannten Bedeutungen haben, und die Verbindung der Formel IM mit einer Aminosäure der Formel IV,
Figure imgf000062_0001
where R2 and PG have the meanings given in the compound of the formula I, and the compound of the formula III with an amino acid of the formula IV,
Figure imgf000062_0002
wobei R3 die in der Verbindung der Formel I genannte Bedeutung hat, zu einer Verbindung der Formel V umsetzt,
Figure imgf000062_0002
where R 3 has the meaning given in the compound of the formula I, to give a compound of the formula V,
Figure imgf000062_0003
wobei R2, R3 und PG die in der Verbindung der Formel I genannten Bedeutungen haben, anschließend wird die Verbindung der Formel V mit einem Amin der Formel NH(R6)2Wθbei R6 die in der Verbindung der Formel I genannte Bedeutung hat, zu einer Verbindung der Formel VI umgesetzt
Figure imgf000062_0003
wherein R2, R3 and PG have the meanings given in the compound of formula I, then the compound of formula V with an amine of the formula NH (R6) 2Wθbei R6 has the meaning mentioned in the compound of formula I, to a compound of Formula VI implemented
Figure imgf000062_0004
wobei R2, R3, R4 und PG die in der Verbindung der Formel I genannten Bedeutungen haben, und dann in eine Verbindung der Formel I überführt, oder b) eine Verbindung der Formel Il wird mit einer Verbindung der Formel IX,
Figure imgf000062_0004
where R 2, R 3, R 4 and PG have the meanings given in the compound of the formula I, and then converted into a compound of the formula I, or b) a compound of the formula II is reacted with a compound of the formula IX,
O R4-^ NH2 (IX)OR 4 - ^ NH 2 (IX)
R3 wobei R3, R4 und PG die in der Verbindung der Formel I genanntenR3 wherein R3, R4 and PG mentioned in the compound of formula I.
Bedeutungen haben, zu einer Verbindung der Formel X umgesetzt,
Figure imgf000063_0001
wobei R2, R3, R4 und PG die in der Verbindung der Formel I genannten Bedeutungen haben, und dann in eine Verbindung der Formel I überführt, oder c) eine nach den Verfahren a) oder b) hergestellte Verbindung der Formel I, oder eine geeignete Vorstufe der Formel I, die aufgrund ihrer chemischenMeanings have been converted to a compound of formula X,
Figure imgf000063_0001
where R 2, R 3, R 4 and PG have the meanings given in the compound of the formula I, and then converted into a compound of the formula I, or c) a compound of the formula I prepared according to the process a) or b), or a suitable Precursor of the formula I, due to its chemical
Struktur in enantiomeren Formen auftritt, durch Salzbildung mit enantiomerenreinen Säuren oder Basen, Chromatographie an chiralen Stationärphasen oder Derivatisierung mittels chiraler enantiomerenreinen Verbindungen wie Aminosäuren, Trennung der somit erhaltenen Diastereomeren, und Abspaltung der chiralen Hilfsgruppen in die reinenStructure occurs in enantiomeric forms, by salt formation with enantiomerically pure acids or bases, chromatography on chiral stationary phases or derivatization by means of chiral enantiomerically pure compounds such as amino acids, separation of the diastereomers thus obtained, and cleavage of the chiral auxiliary groups in the pure
Enantiomeren auftrennt, oder d) die nach den Verfahren a) b) oder c) hergestellte Verbindung der Formel I entweder in freier Form isoliert oder im Falle des Vorliegens von sauren oder basischen Gruppen in physiologisch verträgliche Salze umwandelt.Separating enantiomers, or d) the compound of the formula I prepared according to the methods a) b) or c) is either isolated in free form or, in the case of the presence of acidic or basic groups, converted into physiologically acceptable salts.
Die Herstellung der erfindungsgemäßen Verbindungen der Formel (I) erfolgt beispielsweise indem man Aminosäure (II) mit einem Phosgenäquivalent wie Carbonyldiimidazol, Diphosgen, Triphosgen oder Phosgen in einem inerten Lösungsmittel wie DMF oder Dichlormethan behandelt und das dabei entstehende Zwischenprodukt (III) mit einer kommerziell erhältlichen oder durch Entfernung von Schutzgruppen hergestellte Aminosäure (IV) zu einer Verbindung (V) umsetzt, wobei PG wie in der Verbindung der Formel I definiert ist. Anschließend erfolgt die Knüpfung einer Peptidbindung von (V) mit (VI) nach literaturbekannten Verfahren, zum Beispiel in Gegenwart eines Carbodiimids oder unter Voraktivierung mit (V) als Aktivester durch Zusatz von beispielsweise 1-Hydroxybenzotriazol in inerten Lösungsmitteln wie Dimethylformamid (DMF) oder Dichlormethan. Die abschließende Entschützung zu (I) erfolgt wiederum nach den oben zitierten Verfahren zur Schutzgruppenabspaltung gemäß dem folgenden Schema 1.
Figure imgf000064_0001
The compounds of the formula (I) according to the invention are prepared, for example, by treating amino acid (II) with a phosgene equivalent such as carbonyldiimidazole, diphosgene, triphosgene or phosgene in an inert solvent such as DMF or dichloromethane and the resulting intermediate (III) with a commercially available or by deprotecting amino acid (IV) to give a compound (V), wherein PG is as defined in the compound of formula I. Subsequently, the formation of a peptide bond of (V) with (VI) by literature methods, for example in the presence of a carbodiimide or under preactivation with (V) as an active ester by adding, for example, 1-hydroxybenzotriazole in inert solvents such as dimethylformamide (DMF) or dichloromethane , The final deprotection for (I) is again carried out according to the above-cited deprotection methods according to the following Scheme 1.
Figure imgf000064_0001
(VI)(VI)
(D(D
Schema 1Scheme 1
Alternativ hierzu kann die Reihenfolge der Verfahrensschritte auch variiert werden, indem man Verbindungen der Formel (IV) mit NH(R6)2 im Sinne desAlternatively, the order of the process steps can also be varied by reacting compounds of the formula (IV) with NH (R 6) 2 in the sense of
Verfahrenschrittes C umsetzt und anschließend die Verfahrensschritte B und D durchführt.Implemented method step C and then performs the method steps B and D.
° H N H(R6)2 O HO-VN- PG R4 T "PG R4^r N H2 (|χ) ° HNH (R 6 ) 2 OH O -V N - PG R 4 T " PG R 4 ^ r NH 2 (| χ)
R3 Peptidkupplung R3 R3R3 peptide coupling R3 R3
(VII) C(VII) C
(VIII)(VIII)
(III)(III)
(I) (VI)(I) (VI)
Schema 2Scheme 2
Ein weiteres Verfahren zur Herstellung der erfindungsgemäßen Verbindungen gemäß (I) ist die Umsetzung der Verbindungen (IX) mit Verbindungen vom Typ (II) analog zu A. In einem Verfahren gemäß Borghese et al. (Org. Process Res. Dev.2006, 10, 770- 775) werden Verbindungen der Formel X hergestellt, welche anschließend entschützt werden und Verbindungen der Formel I ergeben:A further process for preparing the compounds of the invention according to (I) is the reaction of the compounds (IX) with compounds of the type (II) analogously to A. In a process according to Borghese et al. (Org. Process Res. Dev.2006, 10, 770-775) compounds of the formula X are prepared, which are subsequently deprotected and give compounds of the formula I:
Figure imgf000064_0002
D
Figure imgf000064_0002
D
(I) Schema 3(I) Scheme 3
Unter den Aminen der Formel NH(R6)2 werden kommerziell erhältliche oder nach literaturbekannten Verfahren hergestellte Amine oder Dipeptidderivate verstanden. Die Verbindungen (II) sind kommerziell erhältlich oder können durch Alkylierung von (Benzhydryliden-amino)-essigsäure-tert-butylester in geeigneten Lösungsmittel wie THF oder DMF unter Einwirkung von Basen wie Lithiumhexa-methyldisilazan, KOH, NaOH, CsOH, K2CO3 oder NaH und anschließender Entschützung unter saurenAmines of the formula NH (R 6) 2 are understood as meaning commercially available amines or dipeptide derivatives prepared by methods known from the literature. The compounds (II) are commercially available or can be prepared by alkylation of tert-butyl (benzhydrylidene-amino) -acetate in suitable solvents such as THF or DMF under the action of bases such as lithium hexa-methyldisilazane, KOH, NaOH, CsOH, K2CO3 or NaH and subsequent deprotection under acidic
Bedingungen, beispielsweise in verdünnter Salzsäure oder wässriger Citronensäure erhalten werden (Schema 4, vgl. z.B. J. Ezquerra et al., Tetrahedron Lett. 1993, 34 (52), 8535-8538). Die Verbindungen (Xl) sind kommerziell erhältlich oder literaturbekannt, wobei X eine geeignete Abgangsgruppe wie Brom, lod, Chlor, Tosylat oder Mesylat darstellt.Conditions, for example, in dilute hydrochloric acid or aqueous citric acid (Scheme 4, see, e.g., Ezquerra, J et al., Tetrahedron Lett., 1993, 34 (52), 8535-8538). The compounds (XI) are commercially available or known from the literature, where X represents a suitable leaving group such as bromine, iodine, chlorine, tosylate or mesylate.
Figure imgf000065_0001
Figure imgf000065_0001
Schema 4Scheme 4
Eine nach Schema 1oder 3 hergestellte Verbindung der Formel I, oder eine geeignete Vorstufe der Formel I, die aufgrund ihrer chemischen Struktur in enantiomeren Formen auftritt, kann durch Salzbildung mit enantiomerenreinen Säuren oder Basen, Chromatographie an chiralen Stationärphasen oder Derivatisierung mittels chiraler enantiomerenreinen Verbindungen wie Aminosäuren, Trennung der somit erhaltenen Diastereomeren, und Abspaltung der chiralen Hilfsgruppen in die reinen Enantiomeren aufgetrennt werden (Verfahren b), oder die nach Schema 1 oder 3 hergestellte Verbindung der Formel I kann entweder in freier Form isoliert oder im Falle des Vorliegens von sauren oder basischen Gruppen in physiologisch verträgliche Salze umwandelt werden (Verfahren d). Im Verfahrensschritt c) wird die Verbindung der Formel I, sofern sie als Gemisch von Diastereomeren oder Enantiomeren auftritt oder bei der gewählten Synthese als deren Gemische anfällt, in die reinen Stereoisomeren getrennt, entweder durch Chromatographie an einem gegebenenfalls chiralen Trägermaterial, oder, sofern die racemische Verbindung der Formel I zur Salzbildung befähigt ist, durch fraktionierte Kristallisation der mit einer optisch aktiven Base oder Säure als Hilfsstoff gebildeten diastereomeren Salze. Als chirale Stationärphasen für die dünnschicht- oder säulenchromatographische Trennung von Enantiomeren eignen sich zum Beispiel modifizierte Kieselgelträger (sogenannte Pirkle-Phasen) sowie hochmolekulare Kohlenhydrate wie Triacetylcellulose. Für analytische Zwecke sind nach entsprechender, dem Fachmann bekannter Derivatisierung, auch gaschromatographische Methoden an chiralen Stationärphasen anwendbar. Zur Enantiomerentrennung der racemischen Carbonsäuren werden mit einer optisch aktiven, in der Regel kommerziell erhältlichen Base wie (-)-Nicotin, (+)- und (-)- Phenylethylamin, Chininbasen, L-Lysin oder L-und D-Arginin die unterschiedlich löslichen diastereomeren Salze gebildet, die schwerer lösliche Komponente als Feststoff isoliert, das leichter lösliche Diastereomer aus der Mutterlauge abgeschieden und aus den so gewonnenen diastereomeren Salzen die reinen Enantiomeren gewonnen. Auf prinzipiell gleiche Weise kann man die racemischen Verbindungen der Formel I, die eine basische Gruppe wie eine Aminogruppe enthalten, mit optisch aktiven Säuren, wie (+)-Campher-10-sulfonsäure, D- und L- Weinsäure, D-und L- Milchsäure sowie (+) und (-)-Mandelsäure in die reinen Enantiomeren überführen. Auch kann man chirale Verbindungen, die Alkohol- oder Amin-funktionen enthalten, mit entsprechend aktivierten oder gegebenenfalls N-geschützten enantiomerenreinen Aminosäuren in die entsprechenden Ester oder Amide, oder umgekehrt chiraleA compound of the formula I prepared according to Scheme 1 or 3, or a suitable precursor of the formula I, which occurs in enantiomeric forms because of its chemical structure, can be formed by salt formation with enantiomerically pure acids or bases, chromatography on stationary chiral phases or derivatization using chiral enantiomerically pure compounds such as amino acids , Separation of the thus obtained diastereomers, and cleavage of the chiral auxiliary groups are separated into the pure enantiomers (process b), or the compound of formula I prepared according to Scheme 1 or 3 can either isolated in free form or in the presence of acidic or basic Groups are converted into physiologically acceptable salts (method d). In process step c), the compound of formula I, if it occurs as a mixture of diastereomers or enantiomers or obtained in the selected synthesis as mixtures thereof, separated into the pure stereoisomers, either by chromatography on an optionally chiral support material, or, if the racemic Compound of formula I is capable of salt formation, by fractional crystallization of diastereomeric salts formed with an optically active base or acid as an excipient. Suitable chiral stationary phases for the thin-layer or column chromatographic separation of enantiomers are, for example, modified silica gel carriers (so-called Pirkle phases) and high molecular weight carbohydrates such as triacetylcellulose. For analytical purposes, gas chromatographic methods can also be used on chiral stationary phases according to appropriate derivatization known to the person skilled in the art. To separate the enantiomers of the racemic carboxylic acids with an optically active, usually commercially available base such as (-) - nicotine, (+) - and (-) - phenylethylamine, quinine bases, L-lysine or L- and D-arginine the different soluble formed diastereomeric salts, the less soluble component as a solid isolated, the more readily soluble diastereomer from the mother liquor deposited and recovered from the thus obtained diastereomeric salts, the pure enantiomers. In principle, the racemic compounds of formula I, which contain a basic group such as an amino group, with optically active acids such as (+) - camphor-10-sulfonic acid, D- and L-tartaric acid, D- and L- Convert lactic acid and (+) and (-) - mandelic acid into the pure enantiomers. Also, one can chiral compounds containing alcohol or amine functions, with appropriately activated or optionally N-protected enantiomerically pure amino acids in the corresponding esters or amides, or conversely, chiral
Carbonsäuren mit carboxygeschützten enantiomerenreinen Aminosäuren in die Amide oder mit enantiomerenreinen Hydroxycarbonsäuren wie Milchsäure, in die entsprechenden chiralen Ester überführen. Sodann kann die Chiralität des in enantiomerenreiner Form eingebrachten Aminosäure- oder Alkoholrestes zur Trennung der Isomeren genutzt werden, indem man eine Trennung der nunmehr vorliegenden Diastereomeren durch Kristallisation oder Chromatographie an geeigneten Stationärphasen vornimmt und danach den mitgeführte chiralen Molekülteil mittels geeigneter Methoden wieder abspaltet.Carboxylic acids with carboxy protected enantiomerically pure amino acids in the amides or with enantiomerically pure hydroxycarboxylic acids such as lactic acid, in the corresponding chiral esters. Then, the chirality of introduced in enantiomerically pure form amino acid or alcohol residue can be used to separate the isomers, by separating the now present diastereomers by crystallization or chromatography performs appropriate stationary phases and then splits off the entrained chiral part of the molecule by means of suitable methods.
Weiterhin ergibt sich bei einigen der erfindungsgemäßen Verbindungen die Möglichkeit, zur Herstellung der Gerüststrukturen diastereo- oder enantiomerenreine Ausgangsprodukte einzusetzen. Dadurch können auch andere oder vereinfachte Verfahren zur Aufreinigung der Endprodukte eingesetzt werden. Diese Ausgangsprodukte wurden zuvor nach literatur-bekannten Verfahren enantiomeren- oder diastereomerenrein hergestellt. Das kann insbesondere bedeuten, dass in der Synthese der Grundgerüste entweder enantioselektive Verfahren zum Einsatz kommen, oder aber eine Enantiomeren- (oder Diastereomeren-) Trennung auf früher Synthesestufe und nicht erst auf der Stufe der Endprodukte durchgeführt wird. Ebenso kann eine Vereinfachung der Trennungen dadurch erreicht werden, dass zwei- oder mehrstufig vorgegangen wird.Furthermore, it is possible with some of the compounds according to the invention to use diastereo- or enantiomerically pure starting materials for the preparation of the framework structures. As a result, other or simplified methods for the purification of the end products can be used. These starting materials were previously prepared by literature methods enantiomeren- or diastereomerenrein. This may in particular mean that either enantioselective processes are used in the synthesis of the basic frameworks, or else an enantiomeric (or diastereomeric) separation is carried out at an early stage of the synthesis and not at the stage of the final products. Likewise, a simplification of the separations can be achieved by acting in two or more stages.
Saure oder basische Produkte der Verbindung der Formel I können in Form ihrer Salze oder in freier Form vorliegen. Bevorzugt sind pharmakologisch verträgliche Salze, beispielsweise Alkali- oder Erdalkalimetallsalze wie Hydrochloride, Hydrobromide, Sulfate, Hemisulfate, alle möglichen Phosphate sowie Salze der Aminosäuren, natürlicher Basen oder Carbonsäuren.Acidic or basic products of the compound of formula I may be in the form of their salts or in free form. Preference is given to pharmacologically acceptable salts, for example alkali metal or alkaline earth metal salts such as hydrochlorides, hydrobromides, sulfates, hemisulfates, all possible phosphates and salts of the amino acids, natural bases or carboxylic acids.
Die Herstellung physiologisch vertrag licfier Salze aus zur Salzbildung befähigten Verbindungen der Formel I, einschließlich deren stereoisomeren Formen, gemäß Verfahrensschritt c) erfolgt in an sich bekannter Weise. Die Verbindungen der Formel I bilden mit basischen Reagenzien wie Hydroxiden, Carbonaten, Hydrogencarbonaten, Alkoholaten sowie Ammoniak oder organischen Basen, beispielsweise Trimethyl- oder Triethylamin, Ethanolamin, Diethanolamin oder Triethanolamin, Trometamol oder auch basischen Aminosäuren, etwa Lysin, Ornithin oder Arginin, stabile Alkali-, Erdalkalioder gegebenenfalls substituierte Ammoniumsalze. Sofern die Verbindungen der Formel I basische Gruppen aufweisen, lassen sich mit starken Säuren auch stabile Säureadditionssalze herstellen. Hierfür kommen sowohl anorganische als auch organische Säuren wie Chlorwasserstoff-, Bromwasserstoff-, Schwefel-, Hemischwefel-, Phosphor-, Methansulfon-, Benzolsulfon-, p-Toluolsulfon-, 4- Brombenzol-sulfon-, Cyclohexylamidosulfon-, Trifluormethylsulfon-, 2- Hydroxyethansulfon-, Essig-, Oxal-, Wein-, Bernstein-, Glycerolphosphor-, Milch-, Äpfel-, Adipin-, Citronen-, Fumar-, Malein-, Glucon-, Glucuron- Palmitin-, oder Trifluoressigsäure in Frage.The preparation of physiologically compatible salts of salts of compounds of the formula I capable of salt formation, including their stereoisomeric forms, according to process step c) is carried out in a manner known per se. The compounds of formula I form with basic reagents such as hydroxides, carbonates, bicarbonates, alcoholates and ammonia or organic bases, for example trimethyl or triethylamine, ethanolamine, diethanolamine or triethanolamine, trometamol or basic amino acids, such as lysine, ornithine or arginine, stable alkali , Alkaline earth or optionally substituted ammonium salts. If the compounds of the formula I have basic groups, stable acid addition salts can also be prepared with strong acids. For this purpose, both inorganic and organic acids such as hydrochloric, hydrobromic, sulfuric, hemic-sulfuric, phosphoric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, 4- Bromobenzenesulfone, cyclohexylamidosulfone, trifluoromethylsulfone, 2-hydroxyethanesulfonic, acetic, oxalic, tartaric, succinic, glycerophosphoric, lactic, malic, adipic, citric, fumaric, maleic, glucone -, Glucuron- palmitic acid, or trifluoroacetic acid in question.
Die Erfindung betrifft auch Arzneimittel, gekennzeichnet durch einen wirksamen Gehalt an mindestens einer Verbindung der Formel I und/oder eines physiologisch verträglichen Salzes der Verbindung der Formel I und/oder eine gegebenenfalls stereoisomere Form der Verbindung der Formel I1 zusammen mit einem pharmazeutisch geeigneten und physiologisch verträglichen Trägerstoff, Zusatzstoff und/oder anderen Wirk- und Hilfsstoffen.The invention also relates to pharmaceutical compositions, characterized by an effective content of at least one compound of formula I and / or a physiologically acceptable salt of the compound of formula I and / or an optionally stereoisomeric form of the compound of formula I 1 together with a pharmaceutically acceptable and physiologically compatible carrier, additive and / or other active ingredients and excipients.
Aufgrund der pharmakologischen Eigenschaften eignen sich die erfindungsgemäßen Verbindungen zur Prophylaxe, Sekundär-Prevention und Therapie all solcher Erkrankungen, die durch eine Hemmung von TAFIa behandelbar sind. So eignen sich TAFIa Inhibitoren sowohl für eine prophylaktische als auch für eine therapeutische Anwendung am Menschen. Sie eignen sich sowohl für eine akute Behandlung als auch für eine Langzeittherapie. TAFIa Inhibitoren können eingesetzt werden in Patienten, die an Störungen des Wohlbefindens oder Krankheiten leiden, die mit Thrombosen, Embolien, Hyperkoagulabilität oder fibrotischen Veränderungen einhergehen.On account of the pharmacological properties, the compounds according to the invention are suitable for the prophylaxis, secondary prevention and therapy of all diseases which can be treated by an inhibition of TAFIa. Thus TAFIa inhibitors are suitable both for a prophylactic and for a therapeutic application in humans. They are suitable for both acute treatment and long-term therapy. TAFIa inhibitors may be used in patients suffering from disorders of well-being or diseases associated with thrombosis, embolism, hypercoagulability or fibrotic changes.
Dazu gehören der Myokardinfarkt, die Angina pectoris und alle anderen Formen des akuten Koronarsyndroms, der Schlaganfall, die peripher vaskulären Erkrankungen, die tiefe Venenthrombose, die Lungenembolie, embolische oder thrombotische Ereignisse bedingt durch kardiale Arrhythmien, kardiovaskuläre Ereignisse wie Restenose nach Revaskularisierung, Angioplastie und ähnlichen Eingriffen wie Stentimplantationen und Bypass-Operationen. Weiterhin können TAFIa Inhibitoren eingesetzt werden bei allen Eingriffen, die zu einem Kontakt des Blutes mit Fremdoberflächen führen wie z. B. bei Dialysepatienten und Patienten mit Verweilkathetern. TAFIa Inhibitoren können eingesetzt werden, um die Thrombosegefahr nach chirurgischen Eingriffen wie bei Knie- und Hüftgelenksoperationen zu reduzieren. TAFIa Inhibitoren eignen für die Behandlung von Patienten mit disseminierter intravaskulärer Koagulation, Sepsis und anderen intravaskulären Ereignissen, die mit einer Entzündung einhergehen. Weiterhin eignen sich TAFIa Inhibitoren für die Prophylaxe und Behandlung von Patienten mit Atherosklerose, Diabetes und dem metabolischen Syndrom und deren Folgen. Störungen des hämostatischen Systems (beispielsweise Fibrinablagerungen) wurden impliziert in Mechanismen, die zu Tumorwachstum und Tumormetastasierung führen, sowie bei entzündlichen und degenerativen Gelenkserkrankungen wie der rheumatoiden Arthritis und der Arthrose. TAFIa Inhibitoren eignen sich zur Verlangsamung oder Verhinderung solcher Prozesse.These include myocardial infarction, angina pectoris and all other forms of acute coronary syndrome, stroke, peripheral vascular disease, deep vein thrombosis, pulmonary embolism, embolic or thrombotic events due to cardiac arrhythmias, cardiovascular events such as restenosis after revascularization, angioplasty and the like Surgery such as stent implantation and bypass surgery. Furthermore, TAFIa inhibitors can be used in all procedures that lead to a contact of the blood with foreign surfaces such. As in dialysis patients and patients with indwelling catheters. TAFIa inhibitors can be used to reduce the risk of thrombosis following surgical procedures such as knee and hip joint surgery. TAFIa inhibitors are useful in the treatment of patients with disseminated intravascular coagulation, sepsis, and other intravascular events associated with inflammation. Furthermore, TAFIa inhibitors are suitable for the prophylaxis and treatment of patients with atherosclerosis, diabetes and the metabolic syndrome and their consequences. Disorders of the hemostatic system (eg fibrin deposits) have been implicated in mechanisms leading to tumor growth and tumor metastasis, as well as in inflammatory and degenerative joint diseases such as rheumatoid arthritis and osteoarthritis. TAFIa inhibitors are useful for slowing down or preventing such processes.
Weitere Indikationen für den Einsatz von TAFIa Inhibitoren sind fibrotische Veränderungen der Lunge wie die chronische obstruktive Lungenerkrankung, das adult respiratory distress Syndrome (ARDS) und des Auges wie Fibrinablagerungen nach Augenoperationen. TAFIa Inhibitoren eignen sich auch zur Verhinderung und/oder Behandlung von Narbenbildung.Further indications for the use of TAFIa inhibitors are fibrotic changes of the lung such as the chronic obstructive pulmonary disease, the adult respiratory distress syndrome (ARDS) and the eye such as fibrin deposits after eye surgery. TAFIa inhibitors are also useful in the prevention and / or treatment of scarring.
Die Applikation der erfindungsgemäßen Arzneimittel kann durch orale, inhalative, rektale oder transdermale Applikation oder durch subkutane, intraartikuläre, intraperitoneale oder intravenöse Injektion erfolgen. Bevorzugt ist die orale Applikation. Eine Beschichtung mit TAFIa Inhibitoren von Stents und anderen Oberflächen, die im Körper mit Blut in Kontakt kommen, ist möglich.The application of the medicaments according to the invention can be effected by oral, inhalative, rectal or transdermal administration or by subcutaneous, intra-articular, intraperitoneal or intravenous injection. The oral application is preferred. Coating with TAFIa inhibitors of stents and other surfaces that come in contact with blood in the body is possible.
Die Erfindung betrifft auch ein Verfahren zur Herstellung eines Arzneimittels, das dadurch gekennzeichnet, dass man mindestens eine Verbindung der Formel I mit einem pharmazeutisch geeigneten und physiologisch verträglichen Träger und gegebenenfalls weiteren geeigneten Wirk-, Zusatz- oder Hilfsstoffen in eine geeignete Darreichungsform bringt.The invention also relates to a process for the preparation of a medicament, which comprises bringing at least one compound of the formula I into a suitable administration form with a pharmaceutically suitable and physiologically acceptable carrier and optionally further suitable active substances, additives or excipients.
Geeignete feste oder galenische Zubereitungsformen sind beispielsweise Granulate, Pulver, Dragees, Tabletten, (Mikro)Kapseln, Suppositorien, Sirupe, Säfte, Suspensionen, Emulsionen, Tropfen oder injizierbare Lösungen sowie Präparate mit protrahierter Wirkstoff-Freigabe, bei deren Herstellung übliche Hilfsmittel wie Trägerstoffe, Spreng-, Binde-, Überzugs-, Quellungs-, Gleit- oder Schmiermittel, Geschmacksstoffe, Siißungsmittel und Lösungsvermittler Verwendung finden. Als häufig verwendete Hilfsstoffe seien Magnesiumcarbonat, Titandioxid, Laktose, Mannit und andere Zucker, Talkum, Milcheiweiß, Gelatine, Stärke, Cellulose und ihreSuitable solid or galenic forms of preparation are, for example, granules, powders, dragees, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions, as well as preparations with protracted release of active ingredient, in the preparation of which conventional auxiliaries such as excipients, disintegrants, binders, coating substances, swelling agents, lubricants or lubricants, flavorings, sweeteners and solubilizers are used. Commonly used adjuvants are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and theirs
Derivate, tierische und pflanzliche Öle wie Lebertran, Sonnenblumen-, Erdnuss- oder Sesamöl, Polyethylenglykol und Lösungsmittel wie etwa steriles Wasser und ein- oder mehrwertige Alkohole wie Glycerin, genannt.Derivatives, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycol and solvents such as sterile water and monohydric or polyhydric alcohols such as glycerol, called.
Vorzugsweise werden die pharmazeutischen Präparate in Dosierungseinheiten hergestellt und verabreicht, wobei jede Einheit als aktiven Bestandteil eine bestimmte Dosis der erfindungsgemäßen Verbindung der Formel I enthält. Bei festen Dosierungseinheiten wie Tabletten, Kapseln, Dragees oder Suppositorien, kann diese Dosis bis zu etwa 1000 mg, bevorzugt jedoch etwa 50 bis 300 mg und bei Injektionslösungen in Ampullenform bis zu etwa 300 mg, vorzugsweise aber etwa 10 bis 100 mg, betragen.Preferably, the pharmaceutical preparations are prepared and administered in dosage units, each unit containing as active ingredient a specific dose of the compound of formula I according to the invention. In the case of solid dosage units such as tablets, capsules, dragees or suppositories, this dose may be up to about 1000 mg, but preferably about 50 to 300 mg and for injection solutions in ampoule form up to about 300 mg, but preferably about 10 to 100 mg.
Für die Behandlung eines erwachsenen, etwa 70 kg schweren Patienten sind je nach Wirksamkeit der Verbindung gemäß Formel I, Tagesdosen von etwa 2 mg bis 1000 mg Wirkstoff, bevorzugt etwa 50 mg bis 500 mg indiziert. Unter Umständen können jedoch auch höhere oder niedrigere Tagesdosen angebracht sein. Die Verabreichung der Tagesdosis kann sowohl durch Einmalgabe in Form einer einzelnen Dosierungseinheit oder aber mehrerer kleinerer Dosierungseinheiten als auch durch Mehrfachgabe unterteilter Dosen in bestimmten Intervallen erfolgen.For the treatment of an adult patient weighing about 70 kg, depending on the efficacy of the compound according to formula I, daily doses of about 2 mg to 1000 mg of active ingredient, preferably about 50 mg to 500 mg, are indicated. However, higher or lower daily doses may be appropriate. The administration of the daily dose can be carried out by single administration in the form of a single unit dose or several smaller dosage units as well as by multiple subdivided doses at specific intervals.
TAFIa Inhibitoren können sowohl als Monotherapie als auch in Kombination oder gemeinsam mit allen Antithrombotika (Antikoagulanzien undTAFIa inhibitors can be used both as monotherapy and in combination or together with all antithrombotics (anticoagulants and
Plättchenaggregationshemmer), Thrombolytika (Plasminogenaktivatoren jeglicher Art), anderen profibrinolytisch wirksamen Substanzen, Blutdrucksenkern, Regulatoren des Blutzuckers, Lipidsenkern und Antiarrhythmika verabreicht werden. BeispielePlatelet aggregation inhibitors), thrombolytic agents (plasminogen activators of any kind), other profibrinolytic agents, antihypertensives, regulators of blood sugar, lipid lowering agents and antiarrhythmic agents. Examples
Endprodukte werden in der Regel durch massenspektroskopische Methoden (FAB-, ESI-MS) und 1H-NMR bestimmt, angegeben sind jeweils der Hauptpeak oder die beiden Hauptpeaks. Temperaturangaben in Grad Celsius, Ausb. bedeutet Ausbeute, RT bedeutet Raumtemperatur (21 0C bis 24 0C). Verwendete Abkürzungen sind entweder erläutert oder entsprechen den üblichen Konventionen. Wenn nicht anders aufgeführt, wurden die LC/MS-Analysen unter folgenden Bedingungen durchgeführt:End products are usually determined by mass spectroscopic methods (FAB, ESI-MS) and 1 H-NMR, indicated in each case the main peak or the two main peaks. Temperatures in degrees Celsius, exp. means yield, RT means room temperature (21 0 C to 24 0 C). Used abbreviations are either explained or correspond to the usual conventions. Unless otherwise stated, the LC / MS analyzes were performed under the following conditions:
Methode A: = Methode Säule: YMC Jsphere H80 20x2 mm, Packungsmaterial 4 μm, Laufmittel: CH3CN : H2O + 0,05% Trifluoressigsäure (TFA), Gradient: 4:96 (0 min.) nach 95:5 (2,0 min.) nach 95:5 (2,4 min) nach 4:96 (2,45 min) Fluss: 1 ,0 mL/min., Temperatur. 30 0C.Method A: = Method Column: YMC Jsphere H80 20x2 mm, packing material 4 μm, eluent: CH3CN: H2O + 0.05% trifluoroacetic acid (TFA), gradient: 4:96 (0 min.) To 95: 5 (2.0 min.) to 95: 5 (2.4 min) after 4:96 (2.45 min) flow: 1, 0 mL / min, temperature. 30 0 C.
Methode B: Säuie: YMC Jsphere 33x2,1 mm, Packungsmaterial 4 μm, Laufmittel: CH3CN + 0,05% TFA : H2O + 0,05% TFA, Gradient: 5:95 (0 min.) nach 95:5 (2,5 min.) nach 95:5 (3,0 min), Fluss: 1 ,3 mL/min., Temperatur: 300C.Method B: Acid: YMC Jsphere 33x2.1 mm, packing material 4 μm, eluent: CH3CN + 0.05% TFA: H2O + 0.05% TFA, gradient: 5:95 (0 min.) To 95: 5 (2 , 5 min.) To 95: 5 (3.0 min), flow: 1, 3 mL / min, temperature: 30 ° C.
Methode C: Säule: YMC Jsphere 33x2,1 mm, Packungsmaterial 4 μm, Laufmittel: CH3CN + 0,08% Ameisensäure : H2O + 0,1% Ameisensäure, Gradient: 5:95 (0 min.) nach 95:5 (2,5 min.) nach 95:5 (3,0 min), Fluss: 1 ,3 mL/min., Temperatur: 300C. Methode D: Säule: YMC Jsphere 33x2,1 mm, Packungsmaterial 4 μm, Laufmittel: CH3CN + 0,05% TFA : H2O + 0,05% TFA, Gradient: 5:95 (0-0.5 min.) nach 95:5 (3,5 min.) nach 95:5 (4,0 min), Fluss: 1 ,3 mL/min., Temperatur: 30°C.Method C: Column: YMC Jsphere 33x2.1 mm, packing material 4 μm, eluent: CH 3 CN + 0.08% formic acid: H 2 O + 0.1% formic acid, gradient: 5:95 (0 min.) To 95: 5 (2 ., 1, 3 mL / min temperature::, 5) minutes after the 95: 5 (3.0 min), river. 30 0 C. method D: column: YMC Jsphere 33x2,1 mm, packing material 4 .mu.m, eluent: CH3CN + 0.05% TFA: H2O + 0.05% TFA, gradient: 5:95 (0-0.5 min) after 95: 5 (3.5 min) after 95: 5 (4.0 min), Flow: 1, 3 mL / min, temperature: 30 ° C.
Methode E: Säule: YMC Jsphere 33x2,1 mm, Packungsmaterial 4 μm, Laufmittel:Method E: Column: YMC Jsphere 33x2.1 mm, packing material 4 μm, eluent:
CH3CN + 0,05% TFA : H2O + 0,05% TFA, Gradient: 2:98 (0-1.0 min.) nach 95:5 (5.0 min.) nach 95:5 (6,2 min), Fluss: 1 ,0 mL/min., Temperatur: 300C. Methode F: Säule: YMC Jsphere 33x2,1 mm, Packungsmaterial 4 μm, Laufmittel:CH3CN + 0.05% TFA: H2O + 0.05% TFA, gradient: 2:98 (0-1.0 min) to 95: 5 (5.0 min) to 95: 5 (6.2 min), flow: 1, 0 mL / min, temperature:. 30 0 C. method F: column: YMC Jsphere 33x2,1 mm, packing material 4 .mu.m, eluent:
CH3CN + 0,05% TFA : H2O + 0,05% TFA, Gradient: 5:95 (0 min.) nach 95:5 (3,4 min.) nach 95:5 (4,4 min), Fluss: 1 ,0 mL/min., Temperatur: 30°C. Soweit nicht anders angegeben, wurden chromatographische Trennungen an Kieselgel mit Ethylacetat/Heptan-Gemischen als Laufmittel durchgeführt. Präparative Trennungen an Reversed Phase-(RP)-Kieselgel (HPLC) wurden, soweit nicht anders angegeben, unter folgenden Bedingungen durchgeführt: Säule Merck Hibar RT 250-25 LiChrospher 100 RP-18e 5μm, mobile Phase A: H2O + 0,1% TFA, Phase B: 80%CH3CN + 0.05% TFA: H2O + 0.05% TFA, Gradient: 5:95 (0 min) to 95: 5 (3.4 min) to 95: 5 (4.4 min), Flow: 1, 0 mL / min., Temperature: 30 ° C. Unless otherwise stated, chromatographic separations were performed on silica gel with ethyl acetate / heptane mixtures as eluent. Preparative separations on reversed phase (RP) silica gel (HPLC) were carried out under the following conditions, unless stated otherwise: Column Merck Hibar RT 250-25 LiChrospher 100 RP-18e 5μm, mobile phase A: H2O + 0.1% TFA, phase B: 80%
Acetonitril + 0,1 % TFA1 Fluss 25 ml/ min., 0-7 min. 100% A , 7-22 min. auf 100% B, 22-30 min. 100% B, 30-33 min. auf 100% A, 33-35 min. 100% A. Das Abdampfen von Lösungsmitteln geschah in der Regel unter vermindertem Druck bei 35 0C bis 45 0C am Rotationsverdampfer.Acetonitrile + 0.1% TFA 1 flow 25 ml / min, 0-7 min. 100% A, 7-22 min. at 100% B, 22-30 min. 100% B, 30-33 min. at 100% A, 33-35 min. 100% A. The evaporation of solvents was usually carried out under reduced pressure at 35 0 C to 45 0 C on a rotary evaporator.
Beispiel 1example 1
(S)-6-Amino-2-{3-[(R)-1-(3-methyl-butylcarbamoyl)-2-phenyl-ethyl]-ureido}-hexansäure(S) -6-amino-2- {3 - [(R) -1- (3-methyl-butylcarbamoyl) -2-phenyl-ethyl] -ureido} -hexanoic acid
Hydrochlorid Beispiel 1 a)Hydrochloride Example 1 a)
(RJ-i-^-Methyl-butylcarbamoyl^-phenyl-ethylJ-carbaminsäure-tert-butyl ester Eine Lösung von N-Boc-D-Phenylalanin (2,653g, 10mmol) in Tetrahydrofuran (THF) (8OmL) wurde sukzessive mit 1-Hydroxybenzotriazol-Hydrat (1 ,685g, 11mmol) und N.N'-Dicyclohexylcarbodiimid (DCC, 2,270 g, 11 mmol) versetzt und 2 h bei RT gerührt. Anschließend wurde Isoamylamin (1 ,162mL, 10mmol) zugesetzt und bei RT weitergerührt. Nach Stehenlassen über Nacht wurde abfiltriert, das Filtrat eingeengt, in Ethylacetat aufgenommen, erneut filtriert, sukzessive mit gesättigter NaHCO3-Lösung und 1 N HCl gewaschen, die organische Phase über MgSO4 getrocknet, filtriert und eingeengt. LC/MS-Daten: Rt(min) 1 ,568; berechnet (ber.): [M+H]+ = 335.47 gefunden (gef.): 235.15 (- tert-Butyloxycarbonyl während der Messung) (Methode A) Beispiel 1 b)(RJ-i - ^ - Methyl-butyl-carbamoyl-phenyl-ethyl-j-carbamic acid tert-butyl ester A solution of N-Boc-D-phenylalanine (2.653 g, 10 mmol) in tetrahydrofuran (THF) (8OmL) was added successively with 1 Hydroxybenzotriazole hydrate (1.685 g, 11 mmol) and N.N'-dicyclohexylcarbodiimide (DCC, 2.270 g, 11 mmol) were added and stirred for 2 h at RT followed by addition of isoamylamine (1.162 mL, 10 mmol) and stirring at RT After standing overnight, the mixture was filtered off, the filtrate was concentrated, taken up in ethyl acetate, filtered again, washed successively with saturated NaHCO 3 solution and 1N HCl, the organic phase dried over MgSO 4, filtered and concentrated LC / MS data: R t (min) 1, 568; calculated (calc.): [M + H] + = 335.47 found (found): 235.15 (- tert-butyloxycarbonyl during the measurement) (Method A) Example 1 b)
(R)-2-Amino-N-(3-methyl-butyl)-3-phenyl-propionamid Eine Lösung des Rohprodukts aus Beispiel 1a) (2,710g, 8,103mmol) in Dichlormethan/Trifluoressigsäure (TFA) (6OmL, 1 :1 v/v) wurde 30min bei RT gerührt. Die Lösung wurde eingeengt, in Ethylacetat aufgenommen und mit 1 N HCl gewaschen. Die wässrige Phase wurde mit Kaliumhydroxyd schwach alkalisch gestellt und dreimal mit Ethylacetat extrahiert. Die vereinigten organischen Phasen wurden über MgSO4 getrocknet, filtriert und eingeengt. LC/MS-Daten: Rt(min) 0,978; ber.: [M+H]+ = 235.35 gef.: 235.15 (Methode A) Beispiel 1c) (S)-6-tert-Butoxycarbonylamino-2-{3-[(R)-1-(3-methyl-butylcarbamoyl)-2-phenyl-ethyl]- ureido}-hexansäure-tert-butylester(R) -2-Amino-N- (3-methyl-butyl) -3-phenyl-propionamide. A solution of the crude product from Example 1a) (2.710 g, 8.103 mmol) in dichloromethane / trifluoroacetic acid (TFA) (6OmL, 1: 1 v / v) was stirred at RT for 30 min. The solution was concentrated, taken up in ethyl acetate and washed with 1N HCl. The aqueous phase was made weakly alkaline with potassium hydroxide and extracted three times with ethyl acetate. The combined organic phases were dried over MgSO 4 , filtered and concentrated. LC / MS data: R t (min) 0.978; Calculated: [M + H] + = 235.35 Found: 235.15 (Method A) Example 1c) (S) -6-tert-Butoxycarbonylamino-2- {3 - [(R) -1- (3-methylbutylcarbamoyl) -2-phenyl-ethyl] -ureido} -hexanoic acid tert-butyl ester
Zu einer Lösung von 1 ,1'-Carbonyldiimidazol (0,955g, 5,889mmol) inTo a solution of 1, 1'-carbonyldiimidazole (0.955g, 5.889mmol) in
Dimethylformamid (DMF) (21 mL) wurde das Rohprodukt aus Beispiel 1b) (1 ,380g, 5,889mmol) gegeben und 1h bei RT gerührt. Anschließend wurden TriethylaminDimethylformamide (DMF) (21 mL) was added to the crude product from Example 1b) (1.80 g, 5.889 mmol) and stirred at RT for 1 h. Subsequently, triethylamine
(1 ,633ml_, 11 ,780mmol) und (S)-2-Amino-6-tert-butoxycarbonylamino-hexansäure-tert- butylester Hydrochlorid (1 ,996g, 5,889mmol) hinzugegeben und über Nacht bei RT stehen gelassen. Die Lösung wurde eingeengt, zwischen Wasser und Ethylacetat verteilt, die organische Phase über MgSO4 getrocknet, filtriert und eingeengt. Das erhaltene Rohprodukt wurde über präparative HPLC gereinigt.(1, 633 ml, 11, 780 mmol) and (S) -2-amino-6-tert-butoxycarbonylaminohexanoic acid tert-butyl ester hydrochloride (1.996 g, 5.889 mmol) were added and allowed to stand at RT overnight. The solution was concentrated, partitioned between water and ethyl acetate, the organic phase dried over MgSO 4 , filtered and concentrated. The crude product obtained was purified by preparative HPLC.
LC/MS-Daten: Rt(min) 1 ,757; ber.: [M+H]+ = 563,76 gef.: 563,35 (Methode A)LC / MS data: R t (min) 1, 757; calc .: [M + H] + = 563.76 found: 563.35 (Method A)
Beispiel 1d)Example 1d)
(S)-6-Amino-2-{3-[(R)-1-(3-methyl-butylcarbamoyl)-2-phenyl-ethyl]-ureido}-hexansäure(S) -6-amino-2- {3 - [(R) -1- (3-methyl-butylcarbamoyl) -2-phenyl-ethyl] -ureido} -hexanoic acid
Hydrochlorid Das Produkt aus Beispiel 1c) (0,500g, 0,889mmol) wurde in Dichlormethan/TFAHydrochloride The product of Example 1c) (0.500 g, 0.889 mmol) was dissolved in dichloromethane / TFA
(10mL,1 :1 , v/v) gelöst und bei RT für 2 h gerührt. Die Lösung wurde eingeengt und über präparative HPLC gereinigt. Die vereinigten Produktfraktionen wurden mit 2N HCl versetzt, eingeengt und gefriergetrocknet.(10mL, 1: 1, v / v) and stirred at RT for 2 h. The solution was concentrated and purified by preparative HPLC. The combined product fractions were treated with 2N HCl, concentrated and freeze-dried.
LC/MS-Daten: Rt(min) 0.971 ; ber.: [M+H]+ = 407.54 gef.: 407.30 (Methode A) Die folgenden Beispiele wurden analog zu Beispiel 1 hergestellt:LC / MS data: R t (min) 0.971; Calc .: [M + H] + = 407.54 Found: 407.30 (Method A) The following examples were prepared analogously to Example 1:
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Beispiel 11Example 11
(S)-6-Amino-2-{3-[(R)-2-cyclohexyl-1-(2,4-difIuoro-benzylcarbamoyl)-ethyl]-ureido}- hexansäure(S) -6-Amino-2- {3 - [(R) -2-cyclohexyl-1- (2,4-difluoro-benzylcarbamoyl) -ethyl] -ureido} -hexanoic acid
Beispiel 11a)Example 11a)
(R)-2-Amino-3-cyclohexyl-propansäure Trifluoracetat(R) -2-amino-3-cyclohexyl-propanoic acid trifluoroacetate
Eine Lösung von (R)-N-Boc-2-Amino-3-cyclohexyl-propansäure (3,0 g, 11 ,1 mmol) inA solution of (R) -N-Boc-2-amino-3-cyclohexyl-propanoic acid (3.0 g, 11.1 mmol) in
20 ml CH2CI2 wurde mit 5 ml TFA versetzt und über Nacht bei RT gerührt. Nach vollständiger Entschützung wurde das CH2CI2 abgedampft, der verbleibende Feststoff mit 50 ml H2O versetzt und lyophilisiert. Ausb.: 2,84 g (90%) farbloser Feststoff des20 ml of CH 2 Cl 2 were admixed with 5 ml of TFA and stirred at RT overnight. After complete deprotection, the CH 2 Cl 2 was evaporated, the remaining solid with 50 ml H 2 O and lyophilized. Yield: 2.84 g (90%) of colorless solid
(R)-2-Amino-3-cyclohexyl-Propansäure Trifluoracetates. Beispiel 11b)(R) -2-Amino-3-cyclohexyl-propanoic acid trifluoroacetate. Example 11b)
(S)-6-tert-Butoxycarbonylamino-2-[3-((R)-1-carboxy-2-cyclohexyl-ethyl)-ureido]- hexansäure tert-butyl ester(S) -6-tert-Butoxycarbonylamino-2- [3 - ((R) -1-carboxy-2-cyclohexyl-ethyl) -ureido] -hexanoic acid tert-butyl ester
Kommerzielles (S)-2-Amino-6-tert-butoxycarbonylamino-hexansäure tert-butyl ester hydrochlorid (1 ,95 g, 5,75 mmol) wurde in 30 ml DMF mit NEt3 (0,8 ml, 5,754 mmoi) und 1 ,1 '-Carbonyl-diimidazol (0,933 g, 5,754 mmol) versetzt und 30 min bei RT gerührt. Anschließend wurden (R)-2-Amino-3-cyclohexyl-Propansäure Trifluoracetat (1 ,64 g, 5,754 mmol) und NEt3 (1 ,6 ml, 11 ,5 mmol) zugesetzt und das Gemisch auf 800C bis zum vollständigen Umsatz des intermediär gebildeten Imidazolides erhitzt. Das Produkt wurde durch Flashchromatographie auf Kieselgel (CH2CI2/MeOH-Commercial (S) -2-amino-6-tert-butoxycarbonylamino-hexanoic acid tert-butyl ester hydrochloride (1.95 g, 5.75 mmol) was dissolved in 30 ml of DMF with NEt 3 (0.8 ml, 5.754 mmol) and 1, 1 '-carbonyl diimidazole (0.933 g, 5.754 mmol) and stirred for 30 min at RT. Then, (R) -2-amino-3-cyclohexyl-propanoic acid trifluoroacetate (1, 64 g, 5.754 mmol) and NEt 3 (1, 6 mL, 11 5 mmol) was added and the mixture to 80 0 C until complete Sales of the intermediately formed imidazole heated. The product was purified by flash chromatography on silica gel (CH 2 Cl 2 / MeOH).
Gradient) gereinigt. Ausb.: 2,1 g (73%) des (S)-6-tert-Butoxycarbonylamino-2-[3-((R)- i-carboxy^-cyclohexyl-ethyO-ureidoJ-hexansäure-tert-butylesters.Gradient). Yield: 2.1 g (73%) of (S) -6-tert-butoxycarbonylamino-2- [3 - ((R) -i-carboxy-cyclohexyl-ethy-ureido-1-hexanoic acid tert-butyl ester.
Beispiel 11c) (S)-6-Amino-2-{3-[(R)-2-cyclohexyl-1-(2,4-difluoro-benzylcarbamoyl)-ethyl]-ureido}- hexansäure TrifluoracetatExample 11c) (S) -6-Amino-2- {3 - [(R) -2-cyclohexyl-1- (2,4-difluoro-benzylcarbamoyl) -ethyl] -ureido} -hexanoic acid trifluoroacetate
Eine Lösung von (S)-6-tert-Butoxycarbonylamino-2-[3-((R)-1-carboxy-2-cyclohexyl- ethyl)-ureido]-hexansäure-tert-butyl ester (80 mg, 0,16 mmol) und 2,4-Difluorbenzyl- amin (22,9 mg, 0,16 mmol) in 3 ml CH2CI2 und 1 ml DMF wurde in der angegebenen Reihenfolge mit N-Methylmorpholin (53 μl, 0,48 mmol), 1-Hydroxybenzotriazol (28 mg, 0,208 mmol) und 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimid Hydrochlorid (36,8 mg, 0,192 mmol) versetzt und bei RT etwa 14 h gerührt. Extrahieren mit CH2CI2/H2O, Trocknen der organischen Phase mit MgSO4 und Eindampfen ergab (S)-6-tert- Butoxycarbonylamino-2-{3-[(R)-2-cyclohexyl-1-(2,4-difluorobenzyl-carbamoyl)-ethyl]- ureido}-hexansäure-tert-butylester als Rohprodukt. Das gesamte Rohprodukt wurde in 4 ml CH2CI2 gelöst, mit 1 ml TFA versetzt, nach 4h mit weiteren 0,5 ml TFA versetzt, und etwa 10 h bei RT entschützt. Die Reinigung des entschützten Rohproduktes über präp. HPLC ergab 25 mg (27%) des (S)-6-Amino-2-{3-[(R)-2-cyclohexyl-1-(2,4-difluoro- benzylcarbamoyl)-ethyl]-ureido}-hexansäure Trifluoracetats. Die folgenden Beispiele wurden analog zu Beispiel 11 hergestellt:A solution of (S) -6-tert-butoxycarbonylamino-2- [3 - ((R) -1-carboxy-2-cyclohexyl-ethyl) -ureido] -hexanoic acid tert-butyl ester (80 mg, 0.16 mmol) and 2,4-difluorobenzylamine (22.9 mg, 0.16 mmol) in 3 ml of CH 2 Cl 2 and 1 ml of DMF was reacted in the order indicated with N-methylmorpholine (53 μl, 0.48 mmol). , 1-Hydroxybenzotriazole (28 mg, 0.208 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (36.8 mg, 0.192 mmol) and stirred at RT for about 14 h. Extraction with CH 2 Cl 2 / H 2 O, drying of the organic phase with MgSO 4 and evaporation gave (S) -6-tert-butoxycarbonylamino-2- {3 - [(R) -2-cyclohexyl-1- (2, 4-difluorobenzyl-carbamoyl) -ethyl] - ureido} -hexanoic acid tert-butyl ester as a crude product. The entire crude product was dissolved in 4 ml of CH 2 Cl 2, admixed with 1 ml of TFA, after 4 hours a further 0.5 ml of TFA was added, and deprotected at RT for about 10 h. The purification of the deprotected crude product over prep. HPLC gave 25 mg (27%) of (S) -6-amino-2- {3 - [(R) -2-cyclohexyl-1- (2,4-difluoro-benzylcarbamoyl) -ethyl] -ureido} -hexanoic acid trifluoroacetate. The following examples were prepared analogously to Example 11:
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Beispiel 130:
Figure imgf000100_0001
Example 130:
(S)-6-Amino-2-{3-[(R)-5-benzyloxycarbonylamino-1-((S)-1-carbamoyl-2-methyl- propylcarbamoyl)-pentyl]-ureido}-hexansäure(S) -6-amino-2- {3 - [(R) -5-benzyloxycarbonylamino-1 - ((S) -1-carbamoyl-2-methyl-propylcarbamoyl) -pentyl] -ureido} -hexanoic acid
Beispiel 130a) [(R)-5-tert-Butoxycarbonylamino-5-((S)-1 -carbamoyl-2-methyl- propylcarbamoyl)-pentyl]-carbaminsäure benzylesterExample 130a) [(R) -5-tert-Butoxycarbonylamino-5 - ((S) -1-carbamoyl-2-methyl-propylcarbamoyl) -pentyl] -carbamic acid benzyl ester
Eine Lösung von kommerziell erhältlicher (R)-6-Benzyloxycarbonylamino-2-tert- butoxycarbonylamino-hexansäure (1 g, 2,63 mmol) und kommerziell erhältlichem (S)- 2-Amino-3-methyl-butyramid Hydrochlorid (0,40 g, 2,63 mmol) in 12 ml CH2CI2 und 4 ml DMF wurde in dieser Reihenfolge mit N-Methylmorpholin (0,87 ml, 7,9 mmol), 1- Hydroxybenzotriazol (0,46 g, 3,41 mmol) und 1-(3-Dimethylaminopropyl)-3- ethylcarbodiimid Hydrochlorid (0,65 g, 3,41 mmol) versetzt und etwa 14 h bei RT gerührt. Flashchromatographie (Gradient Heptan/AcOEt nach CH2CI2/MeOH) ergab 1 g des Produktes (79%).A solution of commercially available (R) -6-benzyloxycarbonylamino-2-tert-butoxycarbonylamino-hexanoic acid (1 g, 2.63 mmol) and commercially available (S) -2-amino-3-methyl-butyramide hydrochloride (0.40 g, 2.63 mmol) in 12 mL of CH 2 Cl 2 and 4 mL of DMF was added in that order with N-methylmorpholine (0.87 mL, 7.9 mmol), 1-hydroxybenzotriazole (0.46 g, 3.41 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.65 g, 3.41 mmol) and stirred at RT for about 14 h. Flash chromatography (gradient heptane / AcOEt to CH 2 Cl 2 / MeOH) gave 1 g of the product (79%).
Beispiel 130b)Example 130b)
[(R)-5-Amino-5-((S)-1-carbamoyl-2-methyl-propylcarbamoyl)-pentyl]-carbaminsäure benzyl ester hydrochlorid[(R) -5-Amino-5 - ((S) -1-carbamoyl-2-methyl-propylcarbamoyl) -pentyl] -carbamic acid benzyl ester hydrochloride
Eine Lösung von [(R)-5-tert-Butoxycarbonylamino-5-((S)-1-carbamoyl-2-methyl- propylcarbamoyl)-pentyl]-carbaminsäure benzylester (1 g, 2,09 mmol) in 30 ml CH2CI2 wurde mit 5 ml H2O und 5 ml konz. HCI/H2O versetzt und bis zur vollständigenA solution of [(R) -5-tert-butoxycarbonylamino-5 - ((S) -1-carbamoyl-2-methyl-propylcarbamoyl) -pentyl] -carbamic acid benzyl ester (1 g, 2.09 mmol) in 30 mL of CH 2 CI 2 was concentrated with 5 ml H 2 O and 5 ml conc. Added HCI / H 2 O and until complete
Abspaltung der Boc-Schutzgruppe auf 40 0C erhitzt. Extraktion mit H2O/ CH2CI2,Cleavage of the Boc protecting group heated to 40 0 C. Extraction with H 2 O / CH 2 Cl 2 ,
Trocknen der organischen Phase über MgSO4 und Eindampfen ergab 230 mg (27%) des Produktes.Drying of the organic phase over MgSO 4 and evaporation gave 230 mg (27%) of the product.
Beispiel 130c)Example 130c)
(S)-2-{3-[(R)-5-Benzyloxycarbonylamino-1-((S)-1-carbamoyl-2-methyl-propylcarb- amoyl)-pentyl]-ureido}-6-tert-butoxycarbonylamino-hexansäure-tert-butylester(S) -2- {3 - [(R) -5-Benzyloxycarbonylamino-1 - ((S) -1-carbamoyl-2-methyl-propylcarbamoyl) -pentyl] -ureido} -6-tert-butoxycarbonylamino hexanoic acid tert-butyl ester
Trifluoracetattrifluoroacetate
Kommerziell erhältliches (S)-2-Amino-6-tert-butoxycarbonylamino-hexansäure-tert- butylester Hydrochlorid (89 mg, 0,26 mmol) wurde in 4 ml DMF mit NEt3 (0,12 ml, 0,53 mmol) und 1 ,1 '-Carbonyl-diimidazol (43 mg, 0,26 mmol) versetzt und 1 h bei RT gerührt. Anschließend wurde [(R)-5-Amino-5-((S)-1-carbamoyl-2-methyl- propy!carbamoyl)-pentyl]-carbaminsäure-benzylester Hydrochlorid (100 mg, 0,24 mmol) zugesetzt und das Gemisch bis zum vollständigen Umsatz des intermediär gebildeten Imidazolides auf 80 0C erhitzt. Präp. HPLC ergab 76 mg (39%) des (S)-2- {S-^Ri-δ-Benzyloxycarbonylamino-i-^SJ-i-carbamoyl^-methyl-propylcarbamoyl)- pentylJ-ureidol-ö-tert-butoxycarbonylamino-hexansäure-tert-butylester Trifluoracetats.Commercially available tert-butyl (S) -2-amino-6-tert-butoxycarbonylaminohexanoate hydrochloride (89 mg, 0.26 mmol) was dissolved in 4 ml of DMF with NEt 3 (0.12 ml, 0.53 mmol). and 1, 1 '-carbonyl-diimidazole (43 mg, 0.26 mmol) and stirred for 1 h at RT. Subsequently, [(R) -5-amino-5 - ((S) -1-carbamoyl-2-methyl] propyl! carbamoyl) -pentyl] -carbamic acid benzyl ester hydrochloride (100 mg, 0.24 mmol) was added and the mixture heated to complete conversion of the intermediately formed Imidazolides to 80 0 C. Prep. HPLC gave 76 mg (39%) of the (S) -2- {S->Ri-δ-benzyloxycarbonylamino-i-> SJ-1-carbamoyl-methyl-propylcarbamoyl) -pentyl-ureidol-ot-tert-butyl- Butoxycarbonylamino-hexanoic acid tert-butyl ester trifluoroacetate.
Beispiel 13Od)Example 13Od)
(S)-6-Amino-2-{3-[(R)-5-benzyloxycarbonylamino-1-((S)-1-carbamoyl-2-methyl- propylcarbamoyl)-pentyl]-ureido}-hexansäure Trif!uoracetat (S)-2-{3-[(R)-5-Benzyloxycarbonylamino-1 -((S)-1 -carbamoyl-2-methyl- propylcarbamoyO-pentyll-ureidoJ-θ-tert-butoxycarbonylamino-hexansäure-tert- butylester Trifluoracetat (37 mg, 0,045 mmol) wurde in 5 ml CH2CI2 und 1 ml TFA gelöst und 14 h bei RT gerührt. Präp. HPLC ergab 21 mg (70%) des (S)-6-Amino-2-{3- [(R)-5-benzyloxycarbonylamino-1-((S)-1-carbamoyl-2-methyl-propylcarbamoyl)-pentyl]- ureido}-hexansäure Trifluoracetats.(S) -6-Amino-2- {3 - [(R) -5-benzyloxycarbonylamino-1 - ((S) -1-carbamoyl-2-methyl-propylcarbamoyl) -pentyl] -ureido} -hexanoic acid trifluoroacetate (S) -2- {3 - [(R) -5-Benzyloxycarbonylamino-1 - ((S) -1-carbamoyl-2-methyl-propylcarbamoyl-O-pentyl-ureido] -θ-tert-butoxycarbonylamino-hexanoic acid tert-butyl ester Trifluoroacetate (37 mg, 0.045 mmol) was dissolved in 5 mL CH 2 Cl 2 and 1 mL TFA and stirred at RT for 14 h Prep. HPLC gave 21 mg (70%) of the (S) -6-amino-2- { 3- [(R) -5-benzyloxycarbonylamino-1 - ((S) -1-carbamoyl-2-methyl-propylcarbamoyl) -pentyl] -ureido} -hexanoic acid trifluoroacetate.
LC/MS: R1 (min) = 1 ,17 ber.: [M+H]+ = 551 ,32, gefunden gef.: 551 ,31 (Methode B). Analog zu Beispiel 130 wurden folgende Beispiele hergestellt:LC / MS: R 1 (min) = 1.17 calc .: [M + H] + = 551, 32, found found: 551, 31 (Method B). Analogously to Example 130, the following examples were prepared:
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Beispiel 143Example 143
(S)-6-Amino-2-(3-{(S)-1 -[(S)-1 -((S)-1 -methoxycarbonyl-2-methyl-propylcarbamoyl)-2- methyl-propylcarbamoyl]-2-phenyl-ethyl}-sulfamidyl)-hexansäure(S) -6-Amino-2- (3 - {(S) -1 - [(S) -1 - ((S) -1-Methoxycarbonyl-2-methyl-propylcarbamoyl) -2-methyl-propylcarbamoyl] - 2-phenyl-ethyl} -sulfamidyl) -hexanoic acid
Beispiel 143a) (S)-2-((S)-2-Amino-3-methyl-butyryl-amino)-3-methyl-buttersäuremethyIester 600mg (1 ,65 mmol) kommerziell erhältlicher (S)-2-((S)-2-Benzyloxycarbonylamino -3-methyl-butyrylamino)-3-methyl-buttersäuremethylester (Z-VaI-VaI-OMe) wurde in 10 ml_ Methanol gelöst, mit 20 mg Palladium auf Kohle (10%) versetzt und für 2 h bei RT unter einer Wasserstoffatmosphäre (1bar) gerührt. Die Reaktionsmischung wurde abfiltriert und eingeengt und ergab quantitativ die Titelverbindung. LC/MS: Rt(min) 0,85; ber.: [M+H)+ 231 ,17 gef.: 231,16 (Methode B).Example 143a) (S) -2 - ((S) -2-Amino-3-methyl-butyryl-amino) -3-methyl-butyric acid methyl ester 600 mg (1.65 mmol) of commercially available (S) -2 - ((S) -2 -Benzyloxycarbonylamino -3-methyl-butyrylamino) -3-methyl-butyric acid methyl ester (Z-VaI-VaI-OMe) was dissolved in 10 ml of methanol, treated with 20 mg of palladium on carbon (10%) and for 2 h at RT under a Hydrogen atmosphere (1bar) stirred. The reaction mixture was filtered off and concentrated to give the title compound quantitatively. LC / MS: R t (min) 0.85; calc .: [M + H] + 231, 17 = 231.16 (Method B).
Beispiel 143b) (S)-2-[(S)-2-((S)-2-Benzyloxycarbonylamino-3-phenyl-propionylamino)-3-methyl- butyrylamino]-3-methyl-buttersäuremethylesterExample 143b) (S) -2 - [(S) -2 - ((S) -2-Benzyloxycarbonylamino-3-phenylpropionylamino) -3-methylbutyrylamino] -3-methyl-butyric acid methyl ester
247mg Z-Phe-OH (0,825 mmol, 1eq) wurden in trockenem 10 ml_ DMF bei 0 0C unter Argon gelöst. Anschließend wurden 56 mg 1-Hydroxybenzotriazol (0,5 eq), 221mg 1- Ethyl-3-(dimethylaminopropyl)carbodiimid-Hydrochlohd (1,4 eq) und 346 μl_ Hünigs Base (2,4 eq) zugesetzt und für 30 min gerührt. Anschließend wurden 190 mg der Verbindung aus Beispiel 143a) zugesetzt und die Mischung für 20 h bei RT gerührt. Die Reaktionmischung wurde mit 50 ml_ gesättigter NaHCO3-Lösung versetzt und mit Ethylacetat (2 x 30 ml_) extrahiert. Die organische Phase wurde über Na2SO4 getrocknet, filtriert und eingeengt. Das Rohprodukt wurde an Kieselgel mit Heptan/Ethylacetatgemischen chromatographiert. Man erhielt 314 mg der gewünschten Verbindung. LC/MS: Rt(min) 1 ,85; ber.: [M+H]+ 512.28 gef. 512,36 (Methode B).247mg Z-Phe-OH (0.825 mmol, 1EQ) were dissolved in dry 10 ml of DMF at 0 0 C under argon. Subsequently, 56 mg of 1-hydroxybenzotriazole (0.5 eq), 221 mg of 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride (1.4 eq) and 346 μl of Hünig's base (2.4 eq) were added and stirred for 30 min , Subsequently, 190 mg of the compound from Example 143a) were added and the mixture was stirred for 20 h at RT. The reaction mixture was added with 50 ml of saturated NaHCO 3 solution and extracted with ethyl acetate (2 × 30 ml). The organic phase was dried over Na 2 SO 4 , filtered and concentrated. The crude product was chromatographed on silica gel with heptane / ethyl acetate mixtures. 314 mg of the desired compound were obtained. LC / MS: R t (min) 1, 85; calc .: [M + H] + 512.28 gef. 512.36 (Method B).
Beispiel 143c) (S)-2-[(S)-2-((S)-2-Amino-3-phenyl-propionylamino)-3-methyl-butyrylamino]-3-methyl- buttersäuremethylesterExample 143c) (S) -2 - [(S) -2 - ((S) -2-amino-3-phenylpropionylamino) -3-methylbutyrylamino] -3-methylbutyric acid, methyl ester
Die Z-Entschützung von Z-Phe-Val-Val-OMe zu Phe-Val-Val-OMe wurde wie inThe Z-deprotection of Z-Phe-Val-Val-OMe to Phe-Val-Val-OMe was performed as in
Beispiel 143a) beschrieben und lieferte 247 mg der Titelverbindung durchgeführt.Example 143a) and yielded 247 mg of the title compound.
LC/MS: Rt(min) 1 ,09; ber.: [M+H]+ 378,24 gef. 378,33 (Methode B).LC / MS: R t (min) 1, 09; calc .: [M + H] + 378.24 gef. 378.33 (Method B).
Beispiel 143d)Example 143d)
2-Oxo-oxazolidin-3-sulfonylchlorid Zu einer Lösung von 2,25g Chlorsulfonylisocyanat (15,9 mmol, 1 ,0eq) in Dichlormethan (100 ml_) unter Argon wurde bei 0 °C langsam eine Lösung von 1 ,13 mL 2-Bromethanol (15,9 mmol, 1 ,0 eq) in Dichlormethan (20 mL) so zugegeben, dass die Temperatur 10 0C nicht überstieg. Nach Beendigung der Zugabe wurde für 30 min bei 0 0C weitergerührt. Das so erhaltene Produkt wurde direkt im nächsten Schritt weiter umgesetzt.2-oxo-oxazolidin-3-sulfonyl chloride To a solution of 2.25 g of chlorosulfonyl isocyanate (15.9 mmol, 1.0 eq) in dichloromethane (100 mL) under argon was added slowly at 0 ° C a solution of 1, 13 mL 2-bromoethanol (15.9 mmol, 1, 0 eq) in dichloromethane (20 mL) was added so that the temperature did not exceed 10 0 C. After completion of the addition, stirring was continued for 30 min at 0 ° C. The product thus obtained was further reacted directly in the next step.
Beispiel 143e) (S)-6-tert-Butoxycarbonylamino-2-(2-oxo-oxazolidin-3-sulfonylamino)-hexansäure-tert- butylesterExample 143e) tert-butyl (S) -6-tert-butoxycarbonylamino-2- (2-oxo-oxazolidine-3-sulfonylamino) -hexanoate
Zu der in Beispiel 143d) erhaltenen Lösung wurde eine Suspension von 5,39g H- Lys(Boc)-OtBu-Hydrochlorid (15,9 mmol, 1 ,0 eq) und 7,1 mL Triethylamin (50,9 mmol, 3,2 eq) in Dichlormethan (7OmL) so zugegeben, dass die Temperatur 10 0C nicht überstieg. Nach Beendigung der Zugabe ließ man auf RT kommen und für weitere 2 h rühren. Die Reaktionsmischung wurde dann mit 200 mL 0,2 M Salzsäure versetzt, die organische Phase abgetrennt und mit 100 mL 0,2 M Salzsäure gewaschen und eingeengt. Man erhielt 5,5 g des gewünschten Materials als farbloses Öl, welches bei Stehenlassen kristallisierte. LC/MS: Rt(min) 1 ,76; ber.: [M+H]+ 452,14 gef. 452,18 (Methode B).To the solution obtained in Example 143d) was added a suspension of 5.39 g H-Lys (Boc) -OtBu hydrochloride (15.9 mmol, 1.0 eq) and 7.1 mL triethylamine (50.9 mmol, 3, 2 eq) in dichloromethane (7OmL) was added so that the temperature did not exceed 10 0 C. Upon completion of the addition, it was allowed to come to RT and stir for an additional 2 hours. The reaction mixture was then treated with 200 ml of 0.2 M hydrochloric acid, the organic phase was separated and washed with 100 ml of 0.2 M hydrochloric acid and concentrated. This gave 5.5 g of the desired material as a colorless oil which crystallized on standing. LC / MS: R t (min) 1, 76; calc .: [M + H] + 452,14 gef. 452.18 (Method B).
Beispiel 143f)Example 143f)
(S)-6-tert-Butoxycarbonylamino-2-(3-{(S)-1 -[(S)- 1 -((S)-1 -methoxycarbonyl-2-methyl- propylcarbamoyO^-methyl-propylcarbamoyll^-phenyl-ethylj-sulfamidyO-hexansäure- tert-butyl ester 240 mg Phe-Val-Val-OMe (Verbindung aus Beispiel 143c), 0,636 mmol, 1 eq) wurde mit 345 mg der Verbindung aus Beispiel 143e) in 7 mL Acetonitril gelöst und mit 106 μL Triethylamin versetzt. Das Reaktionsgemisch wurde 20 h bei 80 0C gerührt und nach dem Abkühlen eingedampft. Das Rohprodukt wurde durch Chromatographie an Kieselgel mit Heptan/Ethylacetatgemischen als Laufmittel gereinigt. Es wurden 275 mg der Titelverbindung erhalten.(S) -6-tert-butoxycarbonylamino-2- (3 - {(S) -1 - [(S) -1 - ((S) -1-methoxycarbonyl-2-methyl-propylcarbamoyl-O-methyl-propylcarbamoyl] - tert-butyl phenyl-ethyl-sulfamido-O-hexanoate 240 mg of Phe-Val-Val-OMe (compound from Example 143c), 0.636 mmol, 1 eq) was dissolved in 7 mL of acetonitrile with 345 mg of the compound from Example 143e) and with 106 .mu.L of triethylamine. The reaction mixture was stirred at 80 ° C. for 20 h and, after cooling, evaporated. The crude product was purified by chromatography on silica gel with heptane / ethyl acetate mixtures as eluent. There were obtained 275 mg of the title compound.
LC/MS: Rt(min) 1 ,733; ber.: [M+H]+ 742,41 gef. 742,35 (Methode A). Beispiel 143g)LC / MS: R t (min) 1, 733; calc .: [M + H] + 742.41 gef. 742.35 (Method A). Example 143g)
(S)-6-Amino-2-(3-{(S)-1-[(S)-1-((S)-1-methoxycarbonyl-2-methyl-propylcarbamoyl)-2- methyl-propylcarbamoyl]-2-phenyl-ethyl}-sulfamidyl)-hexansäure Eine Lösung von 270 mg der Verbindung aus Beispiel 143f) in 4mL Dichlormethan/TFA (1 :1, v/v) wurde 2 h bei RT gerührt und anschließend eingedampft. Der Rückstand wurde durch präparative HPLC gereinigt und lieferte 131 mg der Titelverbindung als Trifluoracetat. LC-MS: Rt(min) 1,16; ber: [M+H]+ 586,29 gef. 586,39 (Methode B).(S) -6-Amino-2- (3 - {(S) -1 - [(S) -1 - ((S) -1-methoxycarbonyl-2-methyl-propylcarbamoyl) -2-methyl-propylcarbamoyl] - 2-phenylethyl} sulfamidyl) hexanoic acid A solution of 270 mg of the compound from Example 143f) in 4 mM dichloromethane / TFA (1: 1, v / v) was stirred at RT for 2 h and then evaporated. The residue was purified by preparative HPLC to yield 131 mg of the title compound as trifluoroacetate. LC-MS: R t (min) 1.16; About: [M + H] + 586.29 gef. 586.39 (Method B).
Beispiel 144Example 144
(S)-6-Amino-2-{3-[(R)-1-(bicyclo[2.2.1]hept-2-ylcarbamoyl)-2-cyclohexyl-ethyl]- sulamidyl}-hexansäure(S) -6-Amino-2- {3 - [(R) -1- (bicyclo [2.2.1] hept-2-ylcarbamoyl) -2-cyclohexyl-ethyl] -sulamidyl} -hexanoic acid
Die Titelverbindung wurde analog zu Beispiel 143 unter Einsatz eines kommerziel! erhältlichen endo-Norborbonylamin anstelle des Dipeptids in Beispiel 143c). LC-MS: Rt(min) 1 ,34; ber.: [M+H]+ 473,28 gef. 473,36 (Methode B).The title compound was analogous to Example 143 using a commercial! available endo-norborbonylamine instead of the dipeptide in Example 143c). LC-MS: R t (min) 1, 34; calc .: [M + H] + 473.28 gef. 473.36 (Method B).
Beispiel 145Example 145
(S)-6-Amino-2-[3-((S)-1-cyclohexylcarbamoyl-2-phenyl-ethyl)-sulfamidyl]-hexansäure Die Titelverbindung wurde analog zu Beispiel 143 unter Einsatz eines kommerziell erhältlichen Cyclohexylamins anstelle des Dipeptids in Beispiel 143c). LC-MS: Rt(min) 1 ,20; ber.: [M+H]+ 455,24 gef. 455,33 (Methode B).(S) -6-Amino-2- [3 - ((S) -1-cyclohexylcarbamoyl-2-phenyl-ethyl) -sulfamidyl] -hexanoic acid The title compound was prepared analogously to Example 143 using a commercially available cyclohexylamine in place of the dipeptide in Example 143c). LC-MS: R t (min) 1, 20; calc .: [M + H] + 455.24 gef. 455.33 (Method B).
Analog zu Beispiel 143 wurden folgende Beispiele hergestellt:Analogously to Example 143, the following examples were prepared:
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Beispiel 163Example 163
(S)-6-Amino-2-{[(S)-2-cyclohexyl-1 -((1 R,2S,4R)-1 ,7,7-trimethyl-bicyclo[2.2.1 ]hept-2- ylcarbamoyl)-ethy(sulfamidyl]}-hexansäure 1 ) (S)-6-Benzyloxycarbonylamino-2(2-oxo-oxazoiidin-sulfonylamino)-hexansäure benzylester(S) -6-Amino-2 - {[(S) -2-cyclohexyl-1 - ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-one ylcarbamoyl) -ethyl (sulfamidyl) -hexanoic acid 1) (S) -6-Benzyloxycarbonylamino-2 (2-oxo-oxazoiidene-sulfonylamino) -hexanoic acid benzyl ester
Zu einer Lösung von 5,21 g Chlorsulfonylisocyanat (36,9 mmol, 1 ,0 equiv.) in Dichloromethane (300 mL) wurde bei 00C unter Argon langsam eine Lösung von 2,61 mL 2-Bromethanol (36,9 mmol, 1 ,0 equiv.) in Dichloromethan (20 mL) gegeben, so daß die interne Temperatur unter 10 0C blieb. Anschließend wurde weitere 30 min bei 0 0C gerührt. Zu dieser Lösung wurde eine Lösung von1 5,0 g H-Lys(Z)-OBzL*HCI (36,9 mmol, 1 ,0 equiv.) und 16,5 mL Triethylamin (118,0 mmol, 3,2 equivalente (equiv.)) in 120 mL CH2CI2 getropft, so, daß die Temperatur des Reaktionsgemischs nicht über 10 0C kam. Nach der Zugabe wurde das Eisbad entfernt und die Mischung bei RT 4 h gerührt. Anschließend wurde die organische Lösung dreimal mit 100 mL 0,2M HCl (aq.) gewaschen, über Na2SO4 getrocknet und eingeegngt. Man erhielt 18,4 g der rohen Titelverbindung als farbloses Öl, welches direkt in Schritt 3 weiter eingesetzt wurde. LC-MS: Rt(min) 1 ,82; Ber.: [M+H]+ 520,17 Gef.: 520,30 (Method B). 2) [(S)-2-Cyclohexyl-1-((1R,2S,4R)-1 ,7,7-trimethyl-bicyclo[2.2.1]hept-2-ylcarbamoyl)- ethyl]-carbaminsäure-tert-butylester Zu einer Lösung von 5,0 g (S)-2-tert-Butoxycarbonylamino-3-cyclohexyl-propion-säure (Boc-Cha-OH, 18,4 mmol, 1,0 equiv.) in DMF (60 ml_) wurden bei 0 0C unter Argon 3,53 g 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimid Hydrochlorid (18,4 mmol, 1 ,0 equiv.), 1 ,25 g 1-Hydroxybenzotriazol (9,2 mmol, 0,5 equiv.) und 7,3 ml_ Hünigs Base gegeben und die Mischung wurde 30 min gerührt. Anschließend wurden 2,83 g (R)- (+)-Bornylamin (18,4 mmol, 1 ,0 equiv.) und 3,7 ml_ Hünigs Base zugegeben und die Mischung 16 h bei RT gerührt. Das Reaktionsgemisch wurde gequencht mit NaHCθ3 (gesättigt, aq.) und dreimal mit Ethylacetat extrahiert. Die vereinigten organischen Phasen wurden zweimal mit Wasser gewaschen und über Na2SO4 getrocknet und eingeengt. Reinigung durch Flash-Chromatographie an Kieselgel mitTo a solution of 5.21 g of chlorosulfonyl isocyanate (36.9 mmol, 1 equiv.) In dichloromethanes (300 mL) at 0 0 C under argon slowly a solution of 2.61 mL 2-bromoethanol (36.9 mmol , 1, 0 equiv.) In dichloromethane (20 mL), so that the internal temperature remained below 10 0 C. The mixture was then stirred at 0 0 C for a further 30 min. To this solution was added a solution of 1, 5.0 g H-Lys (Z) -OBzL * HCl (36.9 mmol, 1 equiv.) And 16.5 mL triethylamine (118.0 mmol, 3.2 equiv. equiv.)) in 120 mL CH 2 Cl 2 , so that the temperature of the reaction mixture did not exceed 10 0 C. After the addition, the ice bath was removed and the mixture was stirred at RT for 4 h. The organic solution was then washed three times with 100 ml of 0.2 M HCl (aq.), Dried over Na 2 SO 4 and taken in. This gave 18.4 g of the crude title compound as a colorless oil, which was used directly in step 3. LC-MS: R t (min) 1, 82; Calc .: [M + H] + 520.17. Found: 520.30 (Method B). 2) [(S) -2-Cyclohexyl-1 - ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-ylcarbamoyl) -ethyl] -carbamic acid tert. butyl ester To a solution of 5.0 g of (S) -2-tert-butoxycarbonylamino-3-cyclohexyl-propionic acid (Boc-Cha-OH, 18.4 mmol, 1.0 equiv.) In DMF (60 mL) at 0 0 C under argon 3.53 g of 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride (18.4 mmol, 1 0 equiv.), 1, 25 g of 1-hydroxybenzotriazole (9.2 mmol, 0 , 5 equiv.) And 7.3 ml Hünigs base and the mixture was stirred for 30 min. Subsequently, 2.83 g of (R) - (+) - bornylamine (18.4 mmol, 1.0 equiv.) And 3.7 ml of Hünig's base were added and the mixture was stirred at RT for 16 h. The reaction mixture was quenched with NaHCO 3 (saturated, aq.) And extracted three times with ethyl acetate. The combined organic phases were washed twice with water and dried over Na 2 SO 4 and concentrated. Purification by flash chromatography on silica gel with
Heptan/Ethylacetatgemischen als Eluens ergab 6,58 g (88% Ausbeute) derHeptane / ethyl acetate mixtures as eluent gave 6.58 g (88% yield) of
Titelverbindung als farbloses Öl.Title compound as a colorless oil.
LC-MS: Rt(min) 2,42; Ber.: [M+H]+ 407,33 Gef.: 407,32 (Method B).LC-MS: R t (min) 2.42; Ber .: [M + H] + 407.33 F .: 407.32 (Method B).
3) (S)-2-Amino-3-cyclohexyl-N-((1 R,2S,4R)-1 ,7,7-trimethyl-bicyclo[2.2.1 ]hept-2-yl)- propionamid Trifluoracetat3) (S) -2-Amino-3-cyclohexyl-N - ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-yl) -propionamide trifluoroacetate
Zu einer Lösung von 6,5 g [(S)-2-Cyclohexyl-1-((1 R,2S,4R)-1 ,7,7-trimethyl- bicyclo[2.2.1]hept-2-ylcarbamoyl)-ethyl]-carbaminsäure-tert-butyl ester (16,0 mmol) in 50 mL CH2CI2 wurden unter Argon bei 0 0C langsam 50 mL TFA gegeben. Man ließ auf RT kommen. Nach 3 h wurde das Reaktionsgemisch eingeengt. Die Titelverbindung wurde als schwach gelbes Öl erhalten, welches direkt im nächsten Schritt eingesetzt wurde. LC-MS: Rt(min) 1 ,60; Ber: [M+H]+ 307,27 Gef.: 307,39 (Method C).To a solution of 6.5 g of [(S) -2-cyclohexyl-1 - ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-ylcarbamoyl) ethyl] -carbamic acid tert-butyl ester (16.0 mmol) in 50 mL CH 2 Cl 2 was added under argon at 0 0 C slowly 50 mL TFA. It was allowed to come to RT. After 3 hours, the reaction mixture was concentrated. The title compound was obtained as a pale yellow oil which was used directly in the next step. LC-MS: R t (min) 1, 60; Ber: [M + H] + 307.27 Found: 307.39 (Method C).
4) (S)-6-Benzyloxycarbonylamino-2-{[(S)-2-cyclohexyl-1-((1 R,2S,4R)-1 ,7,7-trimethyl- bicycloß^.ijhept^-ylcarbamoyO-ethylsulfamidylß-hexansäurebenzylester 11 ,63 g (S)-6-Benzyloxycarbonylamino-2(2-oxo-oxazolidine-sulfonylamino)- hexansäurebenzylester (22,4 mmol, 1 ,4 equiv.) und 4,9 g (S)-2-Amino-3-cyclohexyl-N- ((1R,2S,4R)-1 ,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl)-propionamid Trifluoracetat (16,0 mmol, 1 ,0 equiv.) wurden in 80 mL MeCN suspendiert und nach Zugabe von 8,9 mL Et3N wurde die Mischung 20 h unter Rückfluß erhitzt. Nach dem Abkühlen wurde die flüchtigen Bestandteile am Rotationsverdampfer entfernt und der Rückstand durch Flash-Chromatographie an Kieselgel mit Heptan/Ethylacetat-Gemischen als Eluens gereinigt. Man erhielt 9,0 g (76% Ausbeute) der Titelverbindung als farblosen Schaum. LC-MS: Rt(min) 2,61; Ber.: [M+H]+ 739,41 Gef.: 739,43 (Method B).4) (S) -6-Benzyloxycarbonylamino-2 - {[(S) -2-cyclohexyl-1 - ((1R, 2S, 4R) -1, 7,7-trimethylbicycloxy} -hehept ^ -ylcarbamoyO- ethylsulfamidylbenzoic acid benzyl ester 11, 63 g of (S) -6-benzyloxycarbonylamino-2 (2-oxo-oxazolidine-sulfonylamino) -hexanoic acid benzyl ester (22.4 mmol, 1.4 equiv.) and 4.9 g of (S) -2- Amino-3-cyclohexyl-N- ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-yl) -propionamide trifluoroacetate (16.0 mmol, 1.0 equiv The mixture was suspended in 80 mL of MeCN and after addition of 8.9 mL of Et 3 N, the mixture was refluxed for 20 h After cooling, the volatiles were removed on a rotary evaporator and the residue was purified by flash chromatography on silica gel with heptane / Ethyl acetate mixtures as eluent to give 9.0 g (76% yield) of the title compound as a colorless foam. LC-MS: R t (min) 2.61; Ber .: [M + H] + 739.41 F .: 739.43 (Method B).
5) (S)-6-Amino-2-{[(S)-2-cyclohexyl-1-((1 R,2S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]hept-2- ylcarbamoyl)-ethylsulfamidyl]}-hexansäure5) (S) -6-amino-2 - {[(S) -2-cyclohexyl-1 - ((1R, 2S, 4R) -1,7,7-trimethyl-bicyclo [2.2.1] hept 2-ylcarbamoyl) -ethylsulfamidyl] -hexanoic acid
9,0 g (S)-6-Benzyloxycarbonylamino-2-{[(S)-2-cyclohexyl-1-((1 R,2S,4R)-1 ,7,7- trimethyl-bicyclo[2.2.1 ]hept-2-ylcarbamoyl)-ethylsulfamidyl]}-hexansäurebenzylester9.0 g of (S) -6-benzyloxycarbonylamino-2 - {[(S) -2-cyclohexyl-1 - ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-ylcarbamoyl) -ethylsulfamidyl]} - hexanoate
(12,2 mmol) wurden in 90 ml_ Methanol gelöst und nach Zugabe von 600 mg 10%(12.2 mmol) were dissolved in 90 ml_ methanol and after addition of 600 mg 10%
Pd/C 3,5 h bei RT und Normaldruck hydriert. Das Reaktionsgemisch wurde über Celite filtriert und eingeengt. Man erhielt 6,1g (97%) der Titelverbindung als farbloses Öl. 100 mg der Verbindung wurden in 5 mL MeCN gelöst. Nach Zugabe von 50 ml_ Wasser wurde eine Suspension erhalten. Nach Gefriertrocknung erhielt man einen farblosenPd / C for 3.5 h at RT and atmospheric pressure hydrogenated. The reaction mixture was filtered through Celite and concentrated. 6.1 g (97%) of the title compound were obtained as a colorless oil. 100 mg of the compound was dissolved in 5 mL of MeCN. After addition of 50 ml of water, a suspension was obtained. After freeze drying gave a colorless
Feststoff.Solid.
LC-MS: Rt(min) 1 ,70; Ber.: [M+H]+ 515,33 Gef.: 515,35 (Method F).LC-MS: R t (min) 1, 70; Ber .: [M + H] + 515.33 F .: 515.35 (Method F).
1H-NMR (DMSO-dβ) δ 0,68 (s, 3H), 0,82 (s, 3H), 0,83-0,91 (m, 2H), 0,89 (s, 3H), 0,97 1 H-NMR (DMSO-dβ) δ 0.68 (s, 3H), 0.82 (s, 3H), 0.83-0.91 (m, 2H), 0.89 (s, 3H), 0.97
(dd, 1 H, J = 4,8, 13,0 Hz), 1 ,08-1 ,34 (m, 7H), 1 ,35-1 ,55 (m, 5H), 1 ,56-1 ,72 (m, 9H), 1 ,78 (d, 1H, J = 13,0 Hz), 2,04-2,13 (m. 1H), 2,75 (t, 2H, J = 7,1 Hz), 3,51 (t, 1H, J =(dd, 1 H, J = 4.8, 13.0 Hz), 1, 08-1, 34 (m, 7H), 1, 35-1, 55 (m, 5H), 1, 56-1, 72 (m, 9H), 1, 78 (d, 1H, J = 13.0 Hz), 2.04-2.13 (1H m), 2.75 (t, 2H, J = 7.1 Hz ), 3.51 (t, 1H, J =
5,5 Hz), 3,83 (t, 1 H, J = 7,0 Hz), 4,03-4,10 (m, 1 H), 6,91-7,05 (br, 1 H), 7,77 (d, 1 H1 J =5.5 Hz), 3.83 (t, 1H, J = 7.0 Hz), 4.03-4.10 (m, 1H), 6.91-7.05 (br, 1H). , 7.77 (d, 1 H 1 J =
8,8 Hz), 7,5-8,2 (br, 2H).8.8 Hz), 7.5-8.2 (br, 2H).
Beispiel 164 3-(6-Amino-pyridin-3-ylmethyl)-2-[(S)-2-cyclohexyl-1 -((1 R,2S,4R)-1 ,7,7-trimethyl- bicyclo^^.iJhept^-yl-carbamoyO-ethylsulfamidyll-propionsäure 1) 2-Amino-3-(6-tert-butoxycarbonylamino-pyridin-3-yl)-propionsäure-tert-butylester 660 mg N-(Diphenylmethylen)glycin-tert-butylester (2,23 mmol, 1 ,0 equiv) wurden in 15 mL trockenem THF gelöst und unter Argon auf 0 0C gekühlt. Anschließend wurden 2,23 mL 1 M Lithium-hexamethyldisilazan (LiHMDS)-Lösung in THF tropfenweise zugegeben und die Mischung 15 min bei O0C gerührt. Danach wurden 642 mg (5- Bromomethyl-pyridin-2-yl)-carbaminsäure-tert-butyl ester (2,23 mmol, 1 ,0 equiv) zugegeben und die Mischung 2 h bei 0 0C gerührt. Die Mischung wurde mit18 mL ges. Citronensäure gequencht und 1 h bei RT gerührt. Die Mischung wurde mit Ethylacetat (2x 30 mL) extrahiert und die organischen Phasen mit 50 mL 1 M HCl gewaschen. Die wäßrigen Phasen wurden vereint und mit 2M NaOH auf pH 10 gestellt und anschließend 3x mit Ethylacetat extrahiert. Die vereinigten organischen Phasen wurden über Na2SO4 getrocknet und eingeeengt. Der Rückstand wurde durch Flash- Chromatographie an Kieselgel mit Heptan/Ethylacetatgemischen als Eluens gereinigt. Man erhielt 600 mg (80% Ausbeute) der Titelverbindung als farblosen Feststoff. LC-MS: Rt(min) 1 ,06; Ber.: [M+H]+ 338,21 Gef.: 338,27 (Method B). 2) 3-(6-tert-Butoxycarbonylamino-pyridin-3-yl)-2-(2-oxo-oxazolidine-3-sulfonylamino)- propionsäure-tert-butyl esterExample 164 3- (6-Amino-pyridin-3-ylmethyl) -2 - [(S) -2-cyclohexyl-1 - ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo] .iJhept ^ -ylcarbamoyl-ethylsulfamidyl-propionic acid 1) tert-butyl 2-amino-3- (6-tert-butoxycarbonylaminopyridin-3-yl) propionate 660 mg of N- (diphenylmethylene) glycine tert-butyl ester (2.23 mmol, 1 equiv) were dissolved in 15 mL of dry THF and cooled to 0 ° C. under argon. Subsequently, 2.23 ml of 1 M lithium hexamethyldisilazane (LiHMDS) solution in THF were added dropwise and the mixture was stirred at 0 ° C. for 15 min. Thereafter, 642 mg (5-bromomethylpyridin-2-yl) -carbamic acid tert-butyl ester (2.23 mmol, 1 equiv, equiv) were added and the mixture was stirred at 0 ° C. for 2 h. The mixture was saturated with 18 mL. Quenched citric acid and stirred for 1 h at RT. The mixture was extracted with ethyl acetate (2x30 mL) and the organic phases washed with 50 mL 1 M HCl. The aqueous phases were combined and adjusted to pH 10 with 2M NaOH and then extracted 3 times with ethyl acetate. The combined organic phases were dried over Na 2 SO 4 and concentrated. The residue was purified by flash chromatography on silica gel with heptane / ethyl acetate mixtures as eluent. 600 mg (80% yield) of the title compound were obtained as a colorless solid. LC-MS: R t (min) 1, 06; Ber .: [M + H] + 338.21 F .: 338.27 (Method B). 2) 3- (6-tert-Butoxycarbonylamino-pyridin-3-yl) -2- (2-oxo-oxazolidine-3-sulfonylamino) -propionic acid tert-butyl ester
Zu einer Lösung von 251 mg Chlorsulfonylisocyanate (1 ,78 mmol, 1,0 equiv.) in Dichloromethan (10 mL) unter Argon bei 0 0C wurde langsam eine Lösung von 0,126 mL 2-Bromethanol (1 ,78 mmol, 1,0 equiv.) in Dichlormethan (10 mL) getropft, so dass die Temperatur 10 0C nicht überstieg. Nach der Zugabe wurde die Mischung für weitere 30 min bei 0 0C gerührt. Zu dieser Lösung wurde tropfenweise eine Mischung aus 600 mg 2-Amino-3-(6-tert-butoxycarbonylamino-pyridin-3-yl)-propionsäure-tert- butylester (1 ,78 mmol, 1,0 equiv.) und 0,545 mL Triethylamin (3,91 mmol, 2,2 equiv.) in 5 mL CHhCI2 gegeben, so dass die Temperatur nicht über 10 0C stieg. Nach der Zugabe wurde das Eisbad entfernt und das Gemisch weitere 3 h bei RT gerührt. Nach dem Einengen wurde der Rückstand an Kieselgel mit Heptan/Ethylacetatgemischen als Eluens chromatographiert. Man erhielt 320 mg (37% Ausbeute) der Titelverbindung als farblosen Feststoff. LC-MS: Rt(min) 1 ,40; ber.: [M+H]+ 487,19 gef.: 487,26 (Method B). 3) 3-(6-tert-Butoxycarbonylamino-pyridin-3-ylmethyl)-2-[(S)-2-cyclohexyl-1 - ((1 R,2S,4R)-1 ,7,7-trimethyl-bicyclo[2.2.1 ]hept-2-yl-carbamoyl)-ethylsulfamidyl] propionsäure-tert-butylesterTo a solution of 251 mg of chlorosulfonyl isocyanate (1.78 mmol, 1.0 equiv.) In dichloromethane (10 mL) under argon at 0 0 C was slowly added a solution of 0.126 mL 2-bromoethanol (1, 78 mmol, 1.0 equiv.) in dichloromethane (10 mL), so that the temperature did not exceed 10 ° C. After the addition, the mixture was stirred at 0 C for a further 30 min. To this solution was added dropwise a mixture of 600 mg of tert-butyl 2-amino-3- (6-tert-butoxycarbonylaminopyridin-3-yl) propionate (1.78 mmol, 1.0 equiv.) And 0.545 mL added triethylamine (3.91 mmol, 2.2 equiv.) in 5 mL CHhCI 2, so that the temperature did not rise above 10 0 C. After the addition, the ice bath was removed and the mixture was stirred at RT for a further 3 h. After concentration, the residue was chromatographed on silica gel with heptane / ethyl acetate mixtures as eluent. 320 mg (37% yield) of the title compound were obtained as a colorless solid. LC-MS: R t (min) 1, 40; calc .: [M + H] + 487.19 found: 487.26 (Method B). 3) 3- (6-tert-Butoxycarbonylaminopyridin-3-ylmethyl) -2 - [(S) -2-cyclohexyl-1 - ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-yl-carbamoyl) -ethylsulfamidyl] -propionic acid tert-butyl ester
320 mg 3-(6-tert-Butoxycarbonylamino-pyridin-3-yl)-2-(2-oxo-oxazolidin-3- sulfonylamino)-propionsäure-tert-butylester (0,66 mmol, 1 ,0 equiv.) und 277 mg (S)-2- Amino-3-cyclohexyl-N-((1 R,2S,4R)-1 ,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl)-propionamid Trifluoracetat (0,66 mmol, 1 ,0 equiv.), hergestellt wie oben beschrieben, wurden in 12 mL MeCN suspendiert und nach Zugabe von 0,37 mL Et3N für 20 h am Rückfluß erhitzt. Nach dem Abkühlen wurden die flüchtigen Bestandteile abgedampft und der Rückstand durch Flash-Chromatographie an Kieselgel mit Heptan/Ethylacetatgemischen als Eluens gereinigt. Man erhielt 139 mg (30% Ausbeute) der Titelverbindung als farblosen Feststoff. LC-MS: Rt(min) 2,19; Ber.: [M+H]+ 706,42 Gef.: 706,54 (Method B). 4) 3-(6-Amino-pyridin-3-ylmethyl)-2-[(S)-2-cyc!ohexyl-1-((1 R,2S,4R)-1 ,7,7-trimethyl- bicyclo[2.2.1 ]hept-2-yl-carbamoyl)-ethylsulfamidyl]-propionsäure Trifluoracetat 135 mg 3-(6-tert-Butoxycarbonylamino-pyridin-3-y!methyl)-2-[(S)-2-cyclohexyl-1 - ((I R^S^^-I JJ-trimethyl-bicyclo^^.ilhept^-yl-carbamoyO-ethylsulfamidyl] propionsäure-tert-butylester (0,19 mmol) wurden in 1,0 mL CH2Ck gelöst und auf 0 °C gekühlt. Anschließend wurden 0,8 mL TFA zugegeben und die Mischung bei RT gerührt. Nach 1 h wurden die flüchtigen Bestandteile evaporiert und der Rückstand durch RP-HPLC gereinigt. Man erhielt 70 mg (55% Ausbeute) der Titelverbindung als farblosen Feststoff.320 mg of tert-butyl 3- (6-tert-butoxycarbonylaminopyridin-3-yl) -2- (2-oxo-oxazolidine-3-sulfonylamino) propionate (0.66 mmol, 1 equiv.) And 277 mg of (S) -2-amino-3-cyclohexyl-N - ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-yl) -propionamide trifluoroacetate ( 0.66 mmol, 1.0 equiv.), Prepared as described above, were suspended in 12 mL MeCN and, after addition of 0.37 mL Et 3 N for 20 h heated to reflux. After cooling, the volatiles were evaporated and the residue was purified by flash chromatography on silica gel with heptane / ethyl acetate mixtures as eluant. This gave 139 mg (30% yield) of the title compound as a colorless solid. LC-MS: R t (min) 2.19; Ber .: [M + H] + 706.42 Found: 706.54 (Method B). 4) 3- (6-Amino-pyridin-3-ylmethyl) -2 - [(S) -2-cyclohexyl-1 - ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-yl-carbamoyl) ethylsulfamidyl] -propanoic acid trifluoroacetate 135 mg of 3- (6-tert-butoxycarbonylaminopyridin-3-ylmethyl) -2 - [(S) -2-cyclohexyl] 1 - ((1H) - (1H, 3H-trimethyl-bicyclo) -hexyl-1-butyl-carbamoyO-ethylsulfamidyl] -propionic acid tert -butyl ester (0.19 mmol) was dissolved in 1.0 mL CH 2 Ck and The mixture was then cooled to 0 ° C. 0.8 mL TFA was added and the mixture was stirred at RT After 1 h the volatiles were evaporated and the residue was purified by RP-HPLC to give 70 mg (55% yield) of the title compound as colorless solid.
LC-MS: Rt(min) 1 ,61 ; Ber.: [M+H]+ 550,31 Gef.: 550,39 (Method B)1 1 :1-Mischung der Diastereomeren.LC-MS: R t (min) 1, 61; Calc .: [M + H] + 550.31 Found .: 550.39 (Method B) 1 1: 1 mixture of diastereomers.
1H-NMR (DMSO-dβ) δ 0,67 (s, 3H), 0,69 (s, 3H), 0,82 (s, 6H), 0,79-0,92 (m, 4H), 1 ,08- 1 ,39 (m, 16H), 1 ,56-1 ,78 (m, 16H), 2,01 (t, 1H, J = 12,0 Hz), 2,11 (t, I H, J = 12,0 Hz), 2,70 (dd, 1 H1 J = 6,4, 13,9 Hz), 2,79 (dd, 2H1 J = 7,0, 13,9 Hz), 2,94 (dd, 1 H1 J = 5,5, 14,1 Hz), 3,73-3,90 (m, 2H), 4,01-4,13 (m, 1H)1 6,80 (d, 0.5H, J = 8,0 Hz), 6,94 (dd, 2H1 J = 5,3, 8,6 Hz), 7,01 (d, 1H1 J = 9,1 Hz), 7,11 (d, 1H, J = 8,7 Hz), 7,18 (d, 1 H1 J = 9,1 Hz), 7,69-7,74 (m, 3H)1 7,79 (d, 2H, J = 9,4 Hz), 7,85 (dd, 1H1 J = 1 ,9, 9,1 Hz), 7,88-7,99 (br, 4H) 1 H-NMR (DMSO-dβ) δ 0.67 (s, 3H), 0.69 (s, 3H), 0.82 (s, 6H), 0.79-0.92 (m, 4H), 1, 08-1, 39 (m, 16H), 1, 56-1, 78 (m, 16H), 2.01 (t, 1H, J = 12.0 Hz), 2.11 (t, IH, J = 12.0 Hz), 2.70 (dd, 1H 1 J = 6.4, 13.9 Hz), 2.79 (dd, 2H 1 J = 7.0, 13.9 Hz), 2 , 94 (dd, 1 H 1 J = 5.5, 14.1 Hz), 3.73-3.90 (m, 2H), 4.01-4.13 (m, 1H) 1 6.80 ( d, 0.5H, J = 8.0 Hz), 6.94 (dd, 2H 1 J = 5.3, 8.6 Hz), 7.01 (d, 1H 1 J = 9.1 Hz), 7 , 11 (d, 1H, J = 8.7 Hz), 7.18 (d, 1 H 1 J = 9.1 Hz), 7.69 to 7.74 (m, 3H) 1 7.79 (d , 2H, J = 9.4 Hz), 7.85 (dd, 1H 1 J = 1, 9, 9.1 Hz), 7.88-7.99 (br, 4H)
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Pharmakologische BeispielePharmacological examples
Die hergestellten Substanzen wurden mit dem Actichrome Plasma TAFI Activity Kit der Firma American Diagnostica (Pr. Nr. 874) auf Inhibition von TAFIa geprüft. Dabei wurden zu 2 μl 2,5 mM DMSO-Lösung der Substanz 28 μL Testpuffer (2OmM Hepes, 15OmM NaCI, pH 7,4) und 10 μL TAFIa (American Diagnostica Pr.Nr. 874TAFIA; 2,5 /ml) gegeben und 15 Minuten bei RT in einer 96 half-well Mikrotiterplatte inkubiert. Die Enzymreaktion wurde durch Zugabe von 10 μL TAFIa „Developer" (1:2 mit Testpuffer vorverdünnt) gestartet. Der Zeitverlauf der Reaktion wurde bei 420 nm in einemThe substances produced were tested for inhibition of TAFIa with the Actichromic Plasma TAFI Activity Kit from American Diagnostica (Pr. No. 874). In this case, 28 μl of test buffer (20 mM Hepes, 15 mM NaCl, pH 7.4) and 10 μL TAFIA (American Diagnostica No. 874TAFIA, 2.5 / ml) were added to 2 μl of 2.5 mM DMSO solution of the substance Incubated for 15 minutes at RT in a 96-well-well microtiter plate. The enzyme reaction was monitored by addition of 10 μL TAFIa "Developer" (1: 2 with assay buffer prediluted) started. The time course of the reaction was at 420 nm in one
Mikrotiterplattenreader (SpectraMax plus 384; Fa. Molecular Devices) über 15 Minuten verfolgt.Microplate reader (SpectraMax plus 384, Molecular Devices) followed for 15 minutes.
Die IC5o-Werte wurden aus den gemittelten Werten (Doppelbestimmung) einerThe IC 5 o values were calculated from the averaged values (duplicate determination)
Verdünnungsreihe der Substanz mit Hilfe der Software Softmax Pro (Version 4.8; Fa.Dilution series of the substance using the software Softmax Pro (Version 4.8;
Molecular Devices) berechnet.Molecular Devices).
Tabelle 1 zeigt die Ergebnisse. Table 1 shows the results.
Tabelle 1 :Table 1 :
Figure imgf000122_0001
Figure imgf000122_0001

Claims

Patentansprüche claims
1. Verwendung der Verbindung der Formel I1. Use of the compound of the formula I.
Figure imgf000123_0001
und/oder einer stereoisomeren Form der Verbindung der Formel I und/oder
Figure imgf000123_0001
and / or a stereoisomeric form of the compound of formula I and / or
Gemische dieser Formen in jedem Verhältnis, und/oder ein physiologisch verträgliches Salz der Verbindung der Formel I, zur Herstellung eines Arzneimittels zur Prophylaxe, Sekundärprevention und Therapie einer oder mehrerer Erkrankungen, die mit Thrombosen, Embolien, Hyperkoagulabilität oder fibrotischen Veränderungen einhergehen, wobeiMixtures of these forms in any ratio, and / or a physiologically acceptable salt of the compound of formula I, for the manufacture of a medicament for the prophylaxis, secondary prevention and therapy of one or more diseases associated with thrombosis, embolism, hypercoagulability or fibrotic changes, wherein
X für -C(O)- oder -SO2- steht,X is -C (O) - or -SO 2 -,
R1 für 1) Wasserstoffatom,R1 for 1) hydrogen atom,
2) -(C^CeO-Alkyl,2) - (C 1 -C 4) -alkyl,
3) -(Crj-C4)-Alkylen-(C3-Ci2)-Cyc!oa!kyl oder 4) -(C -|-C6)-Alkylen-(C6-C-|4)-Aryl steht,3) - (j Cr C4) alkylene- (C3-Ci2) -Cyc above alkyl or 4) - (C - |! C6) alkylene- (C6-C- | 4) -aryl,
R2 für den Rest der Formel IlR2 for the rest of Formula II
-(A1)m-A2 (II) steht, worin m die ganze Zahl Null oder 1 bedeutet, A1 für 1) -(CH2)n-. worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet,- (A1) m -A2 (II), where m is the integer zero or 1, A1 is 1) - (CH 2) n -. where n is the integer zero, 1, 2 or 3,
2) -NH-(CH2)n-, worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet,2) -NH- (CH 2) n -, where n is the integer zero, 1, 2 or 3,
3) -NH(Ci -C6)-Alkyl)-(CH2)n-, worin n die 9anze Zahl Nu". 1. 2 oder 3 bedeutet,3) -NH (C 1 -C 6) -alkyl) - (CH 2) n -, where n is the number ninth, 1, 2 or 3,
4) -NH((C3-C6)-Cycloalkyl)-(CH2)n-, worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet,4) -NH ((C 3 -C 6) -cycloalkyl) - (CH 2) n -, where n is the integer zero, 1, 2 or 3,
5) -O-(CH2)rr. worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet, oder 6) -(CH2)n-SOx-, worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet und x die ganze Zahl Null, 1 oder 2 bedeutet, steht, A2 für 1) Het, wobei unter Het ein 4- bis 15-gliedriges heterocyclisches Ringsystem mit 4 bis 15 Ringatomen verstanden wird, die in ein, zwei oder drei miteinander verbundenen Ringsystemen vorliegen und die ein, zwei, drei oder vier gleiche oder verschiedene Heteroatome aus der Reihe Sauerstoff, Stickstoff oder Schwefel enthalten und unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch ein -(C-j-C3)-Alkyl, Halogen, -NH2, -CF3 oder -O-CF3 substituiert ist,5) -O- (CH 2) rr. where n is the integer zero, 1, 2 or 3, or 6) - (CH 2) n -SO x -, wherein n is the integer zero, 1, 2 or 3 and x is the integer zero, 1 or 2, A2 is 1) Het, where Het is a 4 - to 15-membered heterocyclic ring system having 4 to 15 ring atoms is understood, which are present in one, two or three interconnected ring systems and containing one, two, three or four identical or different heteroatoms from the series oxygen, nitrogen or sulfur and unsubstituted or independently of one another monosubstituted, disubstituted or trisubstituted by a - (C 1 -C 3) -alkyl, halogen, -NH 2, -CF 3 or -O-CF 3,
2) -(C0-C6)-Alkylen-NH2 ,2) - (C 0 -C 6 ) -alkylene-NH 2 ,
3) -(Ci-C6)-Alkylen-NH-C(=NH)-NH2,3) - (C 1 -C 6) -alkylene-NH-C (= NH) -NH 2,
4) -(C1-C6)-Alkylen-NH-C(=NH)-(Ci-C4)-Alkyl,4) - (C 1 -C 6) -alkylene-NH-C (= NH) - (C 1 -C 4 ) -alkyl,
5) -(C0-C4)-Alkylen-O-NH-C(=NH)-NH2j 6) -(C0-C4)-Alkylen-NH-C(O)-(C1-C6)-Alkyl,5) - (C 0 -C 4) -alkylene-O-NH-C (= NH) -NH 2j 6) - (C 0 -C 4) -alkylene-NH-C (O) - (C 1 -C 6) - alkyl,
7) -(C 1-C6)-Alkylen-N H-C(O)-O-(C 1-C4)-Alkylen-Aryl, wobei Aryl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist,7) - (C 1-C6) alkylene-N HC (O) -O- (C 1-C 4) -alkylene-aryl, wherein aryl is unsubstituted or substituted by -NH 2 or -NH 2, and mono- , is substituted two or three times by R 15,
8) -(C3-C8)-Cycloalkyl-NH2, oder 9) -(Crj-C4)-Alkylen-(C6-C-|4)-Aryl, wobei Aryl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist, steht, R3 für 1) -(Ci-C6)-Alkyl,8) - (C 3 -C 8) -cycloalkyl-NH 2 , or 9) - (C 1 -C 4) -alkylene- (C 6 -C 4) -aryl, where aryl is unsubstituted or substituted by -NH 2 or by NH 2 and mono-, di- or trisubstituted by R 15, R 3 is 1) - (C 1 -C 6) -alkyl,
2) -(Crj-C4)-Alkylen-(C3-C12)-Cycloalkyl, 3) -(C-|-C6)-Alkylen-(C6-C-|4)-Aryl, wobei Aryl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,2) - (Crj-C4) -alkylene- (C3-C12) -cycloalkyl, 3) - (C- | -C6) alkylene- (C6-C- | 4) -aryl, wherein aryl is mono- independently , is substituted two or three times by R 15,
4) -(Cn-C8)-Alkylen-N(R5)-PG,4) - (Cn-C8) -alkylene-N (R5) -PG,
5) -(Ci-C6)-Alkylen-NH-C(O)-O-(Ci-C4)-Alkylen-Aryl, wobei Aryl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist, 6) -(Co-C4)-Alkylen-(C6-Ci4)-Aryl-(Co-C4)-Alkylen-N(R5)-PG,5) - (C 1 -C 6) -alkylene-NH-C (O) -O- (C 1 -C 4 ) -alkylene-aryl, where aryl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15, 6) - (C o -C 4 ) -alkylene- (C 6 -C 14) -aryl (C 1 -C 4 ) -alkylene-N (R 5) -PG,
7) -(C0-C8)-Alkylen-O-PG,7) - (C 0 -C 8) -alkylene-O-PG,
8) -(C0-C4)-Alkylen-(C6-Ci4)-Aryl-(Co-C4)-Alkylen-O-PG,8) - (C 0 -C 4 ) -alkylene- (C 6 -C 14) -aryl (Co-C 4 ) -alkylene-O-PG,
9) -(C0-C8)-Alkylen-C(O)-O-PG, 10) -(Co-C4)-Alkylen-(C6-Ci4)-Aryl-(Co-C4)-Alkylen-C(0)-0-PG oder9) - (C 0 -C 8 ) -alkylene C (O) -O-PG, 10) - (C 1 -C 4 ) -alkylene- (C 6 -C 14) -aryl (C 1 -C 4 ) -alkylene C (0) -0-PG or
11) Wasserstoffatom, steht, R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander für 1) Wasserstoffatom, 2) -(C1-Ce)-AIkYl,11) hydrogen, R4 is -N (R6) 2, where R6 are identical or different and independently of one another represent 1) hydrogen atom, 2) - (C 1 -Ce) -alkyl,
3) -(Crj-C4)-Alkylen-(C3-C-|2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R11 , Halogen, -C(O)-O-RH , -(Ci-C4)-A!kyl-O-R11 oder3) - (Crj-C4) -alkylene- (C3-C- | 2) -cycloalkyl, wherein cycloalkyl unsubstituted or independently of one another once, twice, three or four times by R11, halogen, -C (O) -O -RH, - (Ci-C 4 ) -alkyl-O-R11 or
-O-(C-|-C4)-Alkyl substituiert ist, 4) -(Crj-C6)-Alkylen-(C6-C-|4)-Aryl, wobei Aryl und Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R11 ,-O- (C 1 -C 4) -alkyl, 4) - (C 1 -C 6) -alkylene- (C 6 -C 4) -aryl, where aryl and alkylene are unsubstituted or independently of one another, three or four times by R11,
Halogen, -C(O)-O-RH , -(C-|-C4)-Alkyl-O-R11 , -C(O)-N(R8)2 oder -O-Halogen, -C (O) -O-RH, - (C 1 -C 4 ) -alkyl-O-R 11, -C (O) -N (R 8) 2 or -O-
(C-|-C4)-Alkyl substituiert sind, 5) -(C0-C8)-Alkylen-N(R5)-PG, 6) -(Co-C4)-Alkylen-(C6-C-|4)-Aryl-(Co-C4)-Alkyl-N(R5)-PG,(C 1 -C 4) -alkyl, 5) - (C 0 -C 8 ) -alkylene-N (R 5) -PG, 6) - (Co-C 4 ) -alkylene- (C 6 -C- | 4) -aryl (Co-C 4 ) -alkyl-N (R 5) -PG,
7) -(C0-C8)-Alkylen-O-PG,7) - (C 0 -C 8) -alkylene-O-PG,
8) -(C0-C4)-Alkylen-(C6-Ci4)-Aryl-(Co-C4)-Alkyl-O-PG,8) - (C 0 -C 4) -alkylene- (C 6 -C 14) -aryl (Co-C 4 ) -alkyl-O-PG,
9) -(C0-C8)-Alkylen-C(O)-O-R11 ,9) - (C 0 -C 8) -alkylene-C (O) -O-R 11,
10) -(C0-C4)-Alkylen-(C6-C14)-Aryl-(Co-C4)-Alkyl-C(O)-O-PG, 11) -(Crj-C4)-Alkylen-Het, wobei unter Het ein 4- bis 15-gliedriges heterocyclisches Ringsystem verstanden wird mit 4 bis 15 Ringatomen, die in ein, zwei oder drei miteinander verbundenen Ringsystemen vorliegen und die ein, zwei, drei oder vier gleiche oder verschiedene Heteroatome aus der Reihe Sauerstoff, Stickstoff oder Schwefel enthalten, wobei Het oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-RH , -(C<|-C4)-Alkyl-O-R11 oder -O-(C <|-C4)-Alkyl substituiert sind, 12) -(C<|-C3)-Fluoralkyl,10) - (C 0 -C 4) alkylene- (C 6 -C 14 ) aryl- (C 1 -C 4) alkyl C (O) -O-PG, 11) - (C 1 -C 4) alkylene-Het in which Het is understood to mean a 4- to 15-membered heterocyclic ring system having 4 to 15 ring atoms which are present in one, two or three interconnected ring systems and which contain one, two, three or four identical or different heteroatoms from the series oxygen, Nitrogen or sulfur wherein Het or alkylene is unsubstituted or independently of one another mono-, di- or trisubstituted by R11, halogen, -C (O) -O-RH, - (C <| - C 4 ) -alkyl-O-R11 or -O (C 1-C 4) -alkyl, 12) - (C 1-C 3 ) -fluoroalkyl,
13) -(Co-C4)-Alkylen-CH(R11 )-C(O)-NH2,13) - (Co-C 4 ) -alkylene-CH (R 11) -C (O) -NH 2 ,
14) -(C0-C4)-Alkylen-CH(R11)-C(O)-NH-(Ci-C4)-Alkyl,14) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH- (C 1 -C 4 ) -alkyl,
15) -(Co-C4)-Alkylen-CH(R11 )-C(O)-NH-CH(R12)-R13, oder15) - (Co-C4) alkylene-CH (R11) -C (O) -NH-CH (R12) -R13, or
16) Aminosäure, wobei die Bindung der Aminosäure über eine Peptid- Bindung erfolgt und der Carboxyl-Rest der Aminosäure unsubstituiert oder durch PG oder durch -N(R5)2 substituiert ist, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom, an das sie gebunden sind, einen mono- oder bicyclischen Ring mit 4 bis 9 Ringatomen bilden, der gesättigt, teilweise gesättigt oder aromatisch ist, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(C-|-C4)-Alkyl, -C(O)-O-RH ,16) amino acid, wherein the binding of the amino acid takes place via a peptide bond and the carboxyl radical of the amino acid is unsubstituted or substituted by PG or by -N (R5) 2, or the two radicals R6 together with the N-atom to which they are attached form a mono- or bicyclic ring having from 4 to 9 ring atoms which is saturated, partially saturated or aromatic, the ring being unsubstituted or mono- or di-twice by - (C 1 -C 4 ) -alkyl , -C (O) -O-RH,
Halogen, -(C-|-C4)-Alkyl-O-R11 oder Phenyl substituiert ist, R5 für Wasserstoffatom oder-(C-|-C6)-Alkyl steht,Halogen, - (C- | -C4) alkyl-O-R11 or phenyl, R 5 is hydrogen atom or- (C- | -C6) alkyl is,
PG füreine Schutzgruppe für die Amino-, Carboxyl- oder für die Hydroxyfunktion steht, R7 für Wasserstoffatom oder -(C 1 -Ce)-Alkyl steht,PG is a protective group for the amino, carboxyl or for the hydroxyl function, R 7 is hydrogen atom or - (C 1 -C 6) -alkyl,
R8 für Wasserstoffatom oder -(C-|-C6)-Alkyl steht, R9 für Wasserstoffatom oder -(Ci-Ce)-Alkyl steht,R 8 is hydrogen or - (C 1 -C 6) -alkyl, R 9 is hydrogen or - (C 1 -C 6) -alkyl,
R11 und R12 gleich oder verschieden sind und unabhängig voneinander für 1 ) Wasserstoffatom , 2) -(C1-Ce)-AIlCyI,R 11 and R 12 are identical or different and independently of one another represent 1) hydrogen, 2) - (C 1 -C 6) -alkyl,
3) -(C0-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder oder unabhängig voneinander ein-, zwei- oder dreifach durch Halogen, -OH oder -O-(Ci-C4)-Alkyl substituiert ist, 4) -(Co-C4)-Alkylen-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R13, Halogen, -C(O)-O-R13, -(C-|-C4)-Alkyl-O-R13, -O-(Ci-C4)-Alkyl oder -3) - (C 0 -C 4) -alkylene-phenyl, wherein phenyl is unsubstituted or or independently mono-, di- or trisubstituted by halogen, -OH or -O- (Ci-C4) alkyl is substituted, 4) - (C 1 -C 4) -alkylene- (C 3 -C 12) -cycloalkyl, where cycloalkyl is unsubstituted or independently of one another once, twice, three or four times by R 13, halogen, -C (O) -O-R 13, - (C 1 -C 4) -alkyl-O-R 13, -O- (C 1 -C 4) -alkyl or -
(Co-C4)-Alkylen-Phenyl substituiert ist, 5) -(Co-C4)-Alkylen-C(0)-N(R13)2 oder(Co-C4) alkylene-phenyl, 5) - (Co-C 4) -alkylene-C (0) -N (R13) 2, or
6) -(Crj-C4)-Alkylen-Indolyl, stehen, R13 für 1 ) Wasserstoff atom,6) - (Crj-C4) -alkylene-indolyl, R13 represents 1) hydrogen atom,
2) -(C-i-C^-Alkyl,2) - (C 1 -C 4) -alkyl,
3) -(C0-C4)-Alkylen-C(O)-O-R14, 4) -(C0-C4)-Alkylen-C(O)-R14 oder3) - (C 0 -C 4 ) -alkylene-C (O) -O-R 14, 4) - (C 0 -C 4) -alkylene-C (O) -R 14 or
5) -(C0-C4)-Alkylen-O-R14 steht,5) - (C 0 -C 4) -alkylene-O-R 14,
R14 für Wasserstoffatom, -(C-|-C4)-Alkyl, -NH2 oder -OH, steht und R15 für Wasserstoffatom, -(C1-C4)-Alkyl, -O-CF3, -NH2, -OH, -CF3 oderR14 is hydrogen, - (C- | -C4) alkyl, -NH 2 or -OH, and R15 stands for hydrogen atom, - (C 1 -C 4) alkyl, -O-CF3, -NH2, -OH , -CF 3 or
Halogen steht.Halogen is available.
2. Verwendung der Verbindung der Formel I gemäß Anspruch 1 , wobei X für -C(O)- steht.2. Use of the compound of formula I according to claim 1, wherein X is -C (O) -.
3. Verwendung der Verbindung der Formel I gemäß Anspruch 1 , wobei X für -SO2- steht.3. Use of the compound of the formula I according to claim 1, wherein X is -SO 2 -.
4. Verwendung der Verbindung der Formel I gemäß Anspruch 2, wobei R1 für 1) Wasserstoffatom oder4. Use of the compound of formula I according to claim 2, wherein R 1 is hydrogen or
2) -(C1-C4)-Alkyl, steht, R2 für 1) -(C1-C6)-Alkylen-NH2,2) - (C 1 -C 4 ) -alkyl, R 2 is 1) - (C 1 -C 6 ) -alkylene-NH 2,
2) -(Crj-C4)-Alkylen-Pyridyl-NH2,2) - (Crj-C4) -alkylene-pyridyl-NH2,
3) -(Cfj-C4)-Alkylen-Piperidinyl-NH2,3) - (Cfj-C4) -alkylene-piperidinyl-NH2,
4) -(C0-C4)-Alkylen-Thiazolyl-NH2,4) - (C 0 -C 4) -alkylene-thiazolyl-NH 2 ,
5) -(C1-C6)-Alkylen-NH-C(=NH)-NH2, 6) -(Co-C4)-Alkylen-(C3-C8)-Cycloalkyl-NH2,5) - (C 1 -C 6) -alkylene-NH-C (= NH) -NH 2 , 6) - (Co-C 4 ) -alkylene- (C 3 -C 8 ) -cycloalkyl-NH 2 ,
7) -(C1-C6)-Alkylen-NH-C(=NH)-(Ci-C4)-Alkyl,7) - (C 1 -C 6 ) -alkylene-NH-C (= NH) - (C 1 -C 4 ) -alkyl,
8) -(Co-C4)-Alkylen-0-NH-C(=NH)-NH2) 8) - (Co-C 4 ) -alkylene-0-NH-C (= NH) -NH 2)
9) -(C1-C6)-Alkylen-NH-C(O)-O-(Ci-C4)-Alkylen-Aryl, wobei Aryl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist,9) - (C 1 -C 6) -alkylene-NH-C (O) -O- (Ci-C 4) -alkylene-aryl, wherein aryl is unsubstituted or substituted by -NH 2 or -NH 2, and mono- , is substituted two or three times by R 15,
10) -(C0-C4)-Alkylen-NH-C(O)-(Ci-C4)-Alkyl,10) - (C 0 -C 4 ) -alkylene-NH-C (O) - (C 1 -C 4 ) -alkyl,
11) -(Co-C4)-Alkylen-(C6-C-|4)-Aryl, wobei Aryl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist, oder11) - (Co-C4) alkylene- (C6-C- | 4) -aryl, wherein aryl is unsubstituted or substituted by -NH 2 or -NH 2, and mono-, di- or trisubstituted by R15 , or
12) -(C<i-C4)-Alkylen-SOx-(Ci-C4)-Alkylen-NH2 worin x die ganze12) - (C <iC 4 ) -alkylene-SO x - (Ci-C 4 ) -alkylene-NH 2 wherein x is the whole
Zahl Null, 1 oder 2 bedeutet, steht, R3 für 1) -(C-|-C4)-Alkyl,Number zero, 1 or 2, R 3 is 1) - (C 1 -C 4 ) -alkyl,
2) -(C0-C4)-Alkylen-(C3-C8)-Cycloalkyl, 3) -(C-|-Cρ)-Alkylen-Aryl, wobei Aryl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,2) - (C 0 -C 4 ) -alkylene- (C 3 -C 8) -cycloalkyl, 3) - (C 1 -C 8) -alkylene-aryl, where aryl independently of one another is substituted once, twice or three times by R 15 is
4) -(C <|-C6)-Alkylen-N H-C(O)-O-(C 1-C4)-Alkylen-Aryl, wobei Aryl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist, 5) -(C1 -C6)-Alkylen-N H-PG,4) - (C <| -C6) alkylene-N HC (O) -O- (C 1-C 4) -alkylene-aryl, wherein aryl is independently mono-, di- or trisubstituted by R15, 5) - (C 1 -C 6 ) -alkylene-N H-PG,
6) -(C1-C6)-Alkylen-O-PG,6) - (C 1 -C 6) -alkylene-O-PG,
7) -(C-i-C^-Alkyl, oder7) - (C 1 -C 4) alkyl, or
8) Wasserstoffatom, steht, wobei PG für t-Butyl-, t-Butyloxycarbonyl oder Benzyloxycarbonyl steht, R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander für8) hydrogen, wherein PG is t-butyl, t-butyloxycarbonyl or benzyloxycarbonyl, R4 is -N (R6) 2 , wherein R6 are the same or different and independently of one another
1) Wasserstoff atom,1) hydrogen atom,
2) -(C-i-C^-Alkyl, 3) -(Co-C4)-Alkylen-(C3-C-|2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R11 , Halogen, -C(O)-O-RH , -(C-|-C4)-Alkyl-O-RH oder -O-(C-|-C4)-Alkyl substituiert ist, 4) -(Co-C4)-Alkylen-C(R11)(R12)-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-RH , -(Ci-C4)-Alkyl-O-R11 oder -O-(C-i-C4)-Alkyl substituiert ist,2) - (C 1 -C 4) alkyl, 3) - (Co-C4) -alkylene- (C3-C- | 2) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently of one another once, twice, three or four times by R11, halogen, -C (O) -O -RH, - (C 1 -C 4 ) -alkyl-O-RH or -O- (C 1 -C 4 ) -alkyl, 4) - (Co-C 4 ) -alkylene-C (R11 ) (R 12) - (C 3 -C 12) -cycloalkyl, where cycloalkyl is unsubstituted or independently of one another mono-, di- or trisubstituted by R 11, halogen, -C (O) -O-RH, - (C 1 -C 4) -alkyl- O-R11 or -O- (Ci-C4) -alkyl is substituted,
5) -(Crj-C4)-Alkylen-Het, wobei unter Het ein 4- bis 15-gliedriges heterocyclisches Ringsystem verstanden wird mit 4 bis 15 Ringatomen, die in ein, zwei oder drei miteinander verbundenen Ringsystemen vorliegen und die ein, zwei, drei oder vier gleiche oder verschiedene Heteroatome aus der Reihe Sauerstoff, Stickstoff oder Schwefel enthalten, wobei Het oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-RH , -(Ci-C4)-Alkyl-O-R11 oder -0-(C1 -C4)-Alkyl substituiert sind,5) - (Crj-C4) -alkylene-Het, wherein Het is a 4- to 15-membered heterocyclic ring system is understood with 4 to 15 ring atoms, which are present in one, two or three interconnected ring systems and the one, two, contain three or four identical or different heteroatoms from the series oxygen, nitrogen or sulfur, wherein Het or alkylene is unsubstituted or independently of one another once, twice or three times by R11, halogen, -C (O) -O-RH, - (Ci C 4 ) -alkyl-O-R 11 or -O- (C 1 -C 4 ) -alkyl,
6) -(Crj-C6)-Alkylen-Aryl, wobei Aryl oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11, Halogen, -C(O)-O-R11 , -(Cn-C4)-Alkyl-O-R11 oder -O-(Ci-C4)-Alkyl substituiert sind, 7) -(Crj-C4)-Alkylen-C(R11)(R12)-Aryl, wobei Aryl oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-RH , -(Crj-C4)-Alkyl-O-R11 oder -O-(C-|-C4)-Alkyl substituiert sind,6) - (Crj-C6) -alkylene-aryl, where aryl or alkylene are unsubstituted or independently of one another mono-, di- or trisubstituted by R11, halogen, -C (O) -O-R11, - (Cn-C4) - Alkyl-O-R11 or -O- (C 1 -C 4 ) -alkyl, 7) - (C 1 -C 4 ) -alkylene-C (R 11) (R 12) -aryl wherein aryl or alkylene is unsubstituted or independently -, di- or trisubstituted by R11, halogen, -C (O) -O-H, - (Cr j-C4) -alkyl-O-R11 or -O- (C- | -C4) substituted alkyl,
8) 1 ,2,3,4-Tetrahydro-naphthalenyl, 9) -(Co-C4)-Alkylen-CH(R11)-C(O)-NH2,8) 1, 2,3,4-tetrahydro-naphthalenyl, 9) - (Co-C4) -alkylene-CH (R11) -C (O) -NH 2 ,
10) -(Co-C4)-Alkylen-CH(R11)-C(O)-NH-(Ci-C4)-Alkyl,10) - (Co-C4) -alkylene-CH (R11) -C (O) -NH- (C 1 -C 4 ) -alkyl,
11) -(C0-C4)-Alkylen-CH(R11)-C(O)-NH-CH(R12)-R13,11) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH-CH (R 12) -R 13,
12) -(Cn-C6)-Alkylen-C(O)-O-R11 , wobei Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch R11 , Halogen, -C(O)-O-R11 , -(C1-C4)-Alkyl-O-R11 oder -O-(C-|-C4)-Alkyl substituiert ist, 13) -(Co-C4)-Alkylen-C(R11 )(R12)-C(O)-O-R11 , oder12) - (Cn-C6) -alkylene-C (O) -O-R11, where alkylene is unsubstituted or independently of one another once or twice by R11, halogen, -C (O) -O-R11, - (C 1 - C4) -alkyl-O-R11 or -O- (C- | -C4) alkyl is substituted, 13) - (Co-C 4) -alkylene-C (R11) (R12) -C (O) -O-R11, or
14) -(Ci-C3)-Fluoralkyl, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom, an das sie gebunden sind, einen mono- oder bicyclischen Ring mit 4 bis 9 Ringatomen bilden, der gesättigt, teilweise gesättigt oder aromatisch ist, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(C<|-C4)-Alkyl, -C(O)-O-R11 ,14) - (Ci-C3) -Fluoralkyl, or the two radicals R6 together with the N-atom to which they are attached form a mono- or bicyclic ring having 4 to 9 ring atoms, the saturated, partially saturated or is aromatic, which ring is unsubstituted or mono- or disubstituted by - (C 1 -C 4) -alkyl, -C (O) -O-R 11,
Halogen, -(C<|-C4)-Alkyl-O-R11 oder Phenyl substituiert ist, R7 für Wasserstoffatom oder -(C-|-C4)-Alkyl steht, R9 für Wasserstoffatom oder -(C-|-C4)-Alkyl steht, R11 und R12 gleich oder verschieden sind und unabhängig voneinander fürHalogen, - (C 1 -C 4) -alkyl-O-R 11 or phenyl, R 7 is hydrogen or - (C 1 -C 4) -alkyl, R 9 is hydrogen or - (C 1 -C 4) - Alkyl, R11 and R12 are the same or different and independently of each other
1) Wasserstoffatom,1) hydrogen atom,
2) -(C1-C4)^IkYl,2) - (C 1 -C 4 ) ^ IkYl,
3) -(Crj-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch Halogen, -OH oder -O-(C-|-C4)-Alkyl substituiert ist,3) - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or independently of one another mono-, di- or trisubstituted by halogen, -OH or -O- (C 1 -C 4) -alkyl,
4) -(Co-C4)-Alkylen-(C3-C-|2)-Cycloalkyl, wobei Cycloalkyi unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R13, Halogen, -C(O)-O-RI 3, -(Ci-C4)-Alkyl-O-R13, -O-(C-|-C4)-Alkyl oder4) - (Co-C4) -alkylene- (C3-C- | 2) -cycloalkyl, wherein Cycloalkyi unsubstituted or independently of one another once, two, three or four times by R13, halogen, -C (O) -O -RI 3, - (Ci-C 4 ) -alkyl-O-R 13, -O- (C-C 4 ) -alkyl or
-(Crj-C4)-Alkylen-Phenyl substituiert ist, 5) -(C0-C4)-Alkylen-C(O)-N(R13)2 oder- (C 1 -C 4 ) -alkylene-phenyl, 5) - (C 0 -C 4 ) -alkylene-C (O) -N (R 13) 2 or
6) -(Cn-C4)-Alkylen-Indolyl, stehen,6) - (Cn-C4) -alkylene-indolyl,
R13 für 1) Wasserstoffatom,R 13 is 1) hydrogen,
2) -(C-i^-Alkyl,2) - (C 1 -C 4) alkyl,
3) -(C0-C4)-Alkylen-C(O)-O-R14, 4) -(C0-C4)-Alkylen-C(O)-R14 oder3) - (C 0 -C 4 ) -alkylene-C (O) -O-R 14, 4) - (C 0 -C 4 ) -alkylene-C (O) -R 14 or
5) -(Cn-C4)-Alkylen-O-R14 steht,5) - (Cn-C4) -alkylene-O-R14,
R14 für Wasserstoffatom, -(C-|-C4)-Alkyl, -NH2 oder -OH, steht und R15 für Wasserstoffatom, -(C<|-C4)-Alkyl, -0-CF3, -NH2, -OH, -CF3 oder Halogen steht. R 14 is hydrogen, - (C 1 -C 4) -alkyl, -NH 2 or -OH, and R 15 is hydrogen, - (C 1 -C 4) -alkyl, -O-CF 3 , -NH 2, -OH, -CF3 or halogen.
5. Verwendung der Verbindung der Formel I gemäß Anspruch 2 oder 4, wobei R1 für 1) Wasserstoffatom oder5. Use of the compound of formula I according to claim 2 or 4, wherein R 1 is hydrogen or
2) -(C<|-C4)-Alkyl, steht, R2 für 1) -(C-|-C6)-Alkylen-NH2, 2) -(C1-C4)-Alkylen-Pyridyl-NH2,2) - (C <| -C4) alkyl, R 2 is 1) - (C- | -C6) alkylene-NH 2, 2) - (C 1 -C 4) -alkylene-pyridyl-NH 2,
3) -(C-|-C4)-Alkylen-Piperidinyl-NH2,3) - (C 1 -C 4) -alkylene-piperidinyl-NH 2,
4) -(C1-C6)-Alkylen-NH-C(=NH)-NH2,4) - (C 1 -C 6 ) -alkylene-NH-C (= NH) -NH 2 ,
5) -(C0-C4)-Alkylen-(C3-C6)-Cycloalkyl-NH2,5) - (C 0 -C 4) -alkylene- (C 3 -C 6 ) -cycloalkyl-NH 2 ,
6) -(C1-C6)-Alkylen-NH-C(=NH)-(Ci-C4)-Alkyl, 7) -(C1-C4)-Alkylen-O-NH-C(=NH)-NH2i 6) - (C 1 -C 6) -alkylene-NH-C (= NH) - (C 1 -C 4 ) -alkyl, 7) - (C 1 -C 4 ) -alkylene-O-NH-C (= NH) -NH 2i
8) -(C-i-C6)-Alkylen-NH-C(O)-O-(Ci-C4)-Alkylen-Phenyl, wobei8) - (C 1 -C 6) -alkylene-NH-C (O) -O- (C 1 -C 4) -alkylene-phenyl, wherein
Phenyl unsubstituiert oder durch unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,Phenyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by R 15 independently of one another,
9) -(C1-C4)-Alkylen-NH-C(O)-(C-(-C6)-Alkyl, 10) -(C-| -C4)-Alkylen-Phenyl, wobei Phenyl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,9) - (C 1 -C 4 ) -alkylene-NH-C (O) - (C - (- C 6 ) -alkyl, 10) - (C 1 -C 4 ) -alkylene-phenyl, wherein phenyl independently is monosubstituted, disubstituted or trisubstituted by R 15,
11) -(C1-C4)-Alkylen-SO2-(C1-C4)-Alkylen-NH2, oder11) - (C 1 -C 4) -alkylene-SO 2 - (C 1 -C 4) -alkylene-NH 2 , or
12) -(C1-C4)-Alkylen-S-(Ci-C4)-Alkylen-NH2, steht, R3 für 1) -(C-)-C4)-Alkyl, 2) -(C1-C4)-Alkylen-(C3-C6)-Cycloalkyl,12) - (C 1 -C 4 ) -alkylene-S- (C 1 -C 4 ) -alkylene-NH 2 , R 3 is 1) - (C -) - C 4 ) -alkyl, 2) - (C 1 -C 4 ) -alkylene- (C 3 -C 6 ) -cycloalkyl,
3) -(C-|-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch - NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch3) - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or substituted by - NH 2 or by -NH 2 and one, two or three times
R15 substituiert ist,R 15 is substituted,
4) -(C1-C6)-Alkylen-NH-C(O)-O-(Ci-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist,4) - (C 1 -C 6) -alkylene-NH-C (O) -O- (Ci-C 4) -alkylene-phenyl, wherein phenyl is unsubstituted or substituted by -NH 2 or -NH 2 and - is substituted by R15, two or three times,
5) Wasserstoffatom steht, R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander für 1 ) Wasserstoffatom ,5) is hydrogen, R4 is -N (R6) 2 , where R6 are the same or different and independently of one another 1) hydrogen atom,
2) -(C-i-C^-Alkyl,2) - (C 1 -C 4) -alkyl,
3) -(Co-C4)-Alkylen-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adamantanyl, Bicyclo[3.1.1]heptanyl, Decahydro-naphthalenyl, Tetrahydronaphthalenyl,3) - (C 1 -C 4) -alkylene- (C 3 -C 12) -cycloalkyl, where cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, bicyclo [3.1.1] heptanyl, decahydro-naphthalenyl, tetrahydronaphthalenyl,
Octahydro-4,7-methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach substituiert ist durch -(Ci-C4)-Alkyl, -C(O)-O-RH oder -(C<|-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch Halogen substituiert ist,Octahydro-4,7-methanoindenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently mono-, di-, tri- or tetra-substituted by - (C 1 -C 4) -alkyl, -C (O ) -O-RH or - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or substituted by halogen,
4) -(Co-C4)-Alkylen-C(R11)(R12)-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adamantanyl, Bicyclo[3.1.1]heptanyl, Decahydro-naphthalenyl, Tetrahydronaphthalenyl, Octahydro-4,7-methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach substituiert ist durch -(C-|-C4)-Alkyl, -C(O)-O-RH oder -(Ci-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch Halogen substituiert ist,4) - (Co-C4) -alkylene-C (R11) (R12) - (C3-C12) -cycloalkyl, where cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, bicyclo [3.1.1] heptanyl, decahydro-naphthalenyl, tetrahydronaphthalenyl, octahydro-4,7-methano-indenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently mono-, di-, tri- or tetra-substituted by - (C- | -C 4) -alkyl, -C (O) -O-RH or - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or substituted by halogen,
5) -(Crj-C4)-Alkylen-Het, wobei Het ausgewählt ist aus der Gruppe Acridinyl, Azepinyl, Azetidinyl, Aziridinyl, Benzimidazalinyl, Benzimidazolyl,5) - (Crj-C4) -alkylene-Het, wherein Het is selected from the group acridinyl, azepinyl, azetidinyl, aziridinyl, benzimidazalinyl, benzimidazolyl,
Benzo[1 ,3]dioxolyl, Benzofuranyl, Benzothiofuranyl, Benzothiophenyl, Benzoxazolyl, Benzthiazolyl, Benztriazolyl, Benztetrazolyl, Benzisoxazolyl, Benzisothiazolyl, Carbazolyl, 4aH-Carbazolyl, Carbolinyl, Chinazolinyl, Chinolinyl, 4H-Chinolizinyl, Chinoxalinyl, Chinuclidinyl, Chromanyl, Chromenyl, Cinnolinyl, Deca-hydrochinolinyl, Dibenzofuranyl, Dibenzothiophenyl,Benzo [1,3] dioxolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, Cinnolinyl, deca-hydroquinolinyl, dibenzofuranyl, dibenzothiophenyl,
Dihydrofuran[2,3-b]-tetrahydrofuranyl, Dihydrofuranyl, Dioxolyl, Dioxanyl, 2H, 6H-1 ,5,2-Dithiazinyl, Furanyl, Furazanyl, Imidazolidinyl, Imidazolinyl, Imidazolyl, 1H-lndazolyl, Indolinyl, Indolizinyl, Indolyl, 3H-lndolyl, Isobenzofuranyl, Isochromanyl, Isoindazolyl, Isoindolinyl, Isoindolyl, Isochinolinyl (Benzimidazolyl), Isothiazolidinyl, 2-lsothiazolinyl, Isothiazolyl, Isoxazolyl,Dihydrofuran [2,3-b] tetrahydrofuranyl, dihydrofuranyl, dioxolyl, dioxanyl, 2H, 6H-1, 5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolidinyl, 2-isothiazolinyl, isothiazolyl, isoxazolyl,
Isoxazolidinyl, 2-lsoxazolinyl, Morpholinyl, Naphthyridinyl, Octahydroisochinolinyl, Oxadiazolyl, 1 ,2,3-Oxadiazolyl, 1 ,2,4-Oxadiazolyl, 1 ,2,5- Oxadiazolyl, 1 ,3,4-Oxadiazolyl, Oxazolidinyl, Oxazolyl, Oxazolidinyl, Oxothiolanyl, Pyrimidinyl, Phenanthridinyl, Phenanthrolinyl, Phenazinyl, Phenothiazinyl, Phenoxathiinyl, Phenoxazinyl, Phthalazinyl, Piperazinyl, Piperidinyl, Pteridinyl, Purynyl, Pyranyl, Pyrazinyl, Pyroazolidinyl, Pyrazolinyl,Isoxazolidinyl, 2-isoxazolinyl, morpholinyl, naphthyridinyl, Octahydroisoquinolinyl, oxadiazolyl, 1, 2,3-oxadiazolyl, 1, 2,4-oxadiazolyl, 1, 2,5-oxadiazolyl, 1, 3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, oxothiolanyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, Phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl,
Pyrazolyl, Pyridazinyl, Pryidooxazolyl, Pyridoimidazolyl, Pyridothiazolyl, Pyridothiophenyl, Pyridinyl, Pyridyl, Pyrimidinyl, Pyrrolidinyl, Pyrrolinyl, 2H- Pyrrolyl, Pyrrolyl, Tetrahydrofuranyl, Tetrahydroisochinolinyl, Tetrahydrochinolinyl, Tetrahydropyridinyl, 6H-1 ,2,5-Thiadazinyl, 1 ,2,3- Thiadiazolyl, 1 ,2,4-Thiadiazolyl, 1 ,2,5-Thiadiazolyl, 1 ,3,4-Thiadiazolyl,Pyrazolyl, pyridazinyl, pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl, 6H-1,2,5-thiadazinyl, 1, 2 3-thiadiazolyl, 1, 2,4-thiadiazolyl, 1, 2,5-thiadiazolyl, 1, 3,4-thiadiazolyl,
Thianthrenyl, Thiazolyl, Thienyl, Thienoimidazolyl, Thienooxazolyl, Thienopyridin, Thienothiazolyl, Thiomorpholinyl, Thiophenyl, Triazinyl, 1 ,2,3- Triazolyl, 1 ,2,3-Triazolyl, 1 ,2,4-Triazolyl, 1 ,2,5-Triazolyl, 1 ,3,4-Triazolyl und Xanthenyl, wobei Het oder Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch -(C-|-C4)-Alkyl substituiert istThianthrenyl, thiazolyl, thienyl, thienoimidazolyl, thienooxazolyl, thienopyridine, thienothiazolyl, thiomorpholinyl, thiophenyl, triazinyl, 1, 2,3-triazolyl, 1, 2,3-triazolyl, 1, 2,4-triazolyl, 1, 2,5- Triazolyl, 1, 3,4-triazolyl and xanthenyl, wherein Het or alkylene is unsubstituted or independently of one another mono- or disubstituted by - (C 1 -C 4) -alkyl
6) -(Ci-C6)-Alkylen-Phenyl, wobei Phenyl oder Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Halogen, Phenyl, -C(O)-O-RH , -(C<|-C4)-Alkyl-O-R11 , -O-(C-|-C4)-Alkyl oder -(C<|-C4)-Alkyl substituiert sind, 7) -(Crj-C4)-Alkylen-C(R11)(R12)-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch Phenyl oder Fluor substituiert ist,6) - (C 1 -C 6) -alkylene-phenyl, where phenyl or alkylene is unsubstituted or independently of one another by halogen, phenyl, -C (O) -O-RH, - (C <| -C 4 ) - Alkyl-O-R11, -O- (C 1 -C 4 ) -alkyl or - (C 1 -C 4 ) -alkyl, 7) - (C 1 -C 4 ) -alkylene-C (R 11) (R12) -phenyl, where phenyl is unsubstituted or independently of one another mono-, di- or trisubstituted by phenyl or fluorine,
8) 1 ,2,3,4-Tetrahydro-naphthalenyl,8) 1, 2,3,4-tetrahydro-naphthalenyl,
9) -(C0-C4)-Alkylen-CH(R11 )-C(O)-NH2, 10) -(C0-C4)-Alkylen-CH(R11)-C(O)-NH-(Ci-C4)-Alkyl,9) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH 2 , 10) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH - (Ci-C4) alkyl,
11) -(C0-C4)-Alkylen-CH(R11)-C(O)-NH-CH(R12)-R13,11) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH-CH (R 12) -R 13,
12) -(C-|-C6)-Alkylen-C(O)-O-R11 , wobei Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Halogen, Phenyl, -C(O)-O-RH , -(C-|-C4)-Alkyl-O-R11, -O-(C<|-C4)-Alkyl oder -(C-|-C4)-Alkyl substituiert ist,12) - (C 1 -C 6) alkylene-C (O) -O-R 11, wherein alkyls are unsubstituted or independently of one another by halogen, phenyl, -C (O) -O-RH, - (C C 1 -C 4 ) -alkyl-O-R 11, -O- (C 1 -C 4 ) -alkyl or-C 1 -C 4 -alkyl,
13) -(C0-C4)-Alkylen-C(R11 )(R12)-C(O)-O-R11 , oder 14) -(C-|-C3)-Fluoralkyl, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom an das sie gebunden sind einen Mono- oder Bicyclischen Ring bilden ausgewählt aus der Gruppe Pyrrolidin, Piperidin, 2-Aza-bicyclo[3.2.2]nonan und 7-Aza-bicyclo[2.2.1]hep-tan, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(C-|-C4)-Alkyl, -13) - (C 0 -C 4 ) -alkylene-C (R 11) (R 12) -C (O) -O-R 11, or 14) - (C 1 -C 3) -fluoroalkyl, or the two radicals R 6 together with the N-atom to which they are attached form a mono- or bicyclic ring selected from the group pyrrolidine, piperidine, 2-aza bicyclo [3.2.2] nonane and 7-azabicyclo [2.2.1] hep-tane, the ring being unsubstituted or mono- or disubstituted by - (C 1 -C 4) -alkyl,
C(O)-O-RH , -(C«|-C4)-Alkyl-O-R11 oder Phenyl substituiert ist, R7 für Wasserstoffatom oder -(C-|-C4)-Alkyl steht, R9 für Wasserstoffatom oder -(C-|-C4)-Alkyl steht,C (O) -O-RH, - (C 1 -C 4) -alkyl-O-R 11 or phenyl, R 7 is hydrogen or - (C 1 -C 4) -alkyl, R 9 is hydrogen or - ( C 1 -C 4) -alkyl,
R11 und R12 gleich oder verschieden sind und unabhängig voneinander für 1) Wasserstoffatom,R 11 and R 12 are identical or different and independently of one another represent 1) hydrogen atom,
2) -(C1-C4J-AIkYl,2) - (C 1 -C 4 ) -alkyl,
3) -(Co-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch -OH, Halogen oder -O-(C-|-C4)-Alkyl substituiert ist, 4) -(Crj-C4)-Alkylen-(C3-C-|2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adamantanyl, Bicyclo[3.1.1]heptanyl, Octahydro-4,7-methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch -(C-j-C^-Alkyl, -C(O)-O-RI 3 oder Phenyl substituiert ist, oder3) - (Co-C 4 ) -alkylene-phenyl, where phenyl is unsubstituted or independently of one another monosubstituted, disubstituted or trisubstituted by -OH, halogen or -O- (C 1 -C 4) -alkyl, 4) - (Crj-C4) -alkylene- (C3-C- | 2) -cycloalkyl, wherein cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, bicyclo [3.1.1] heptanyl, octahydro-4,7 -methano-indenyl or bicyclo [2.2.1] heptanyl and wherein cycloalkyl is unsubstituted or substituted independently of one another once, twice, three or four times by - (C 1 -C 4 -alkyl, -C (O) -O-RI 3 or phenyl is, or
5) -(Crj-C4)-Alkylen-Indolyl, stehen,5) - (Crj-C4) -alkylene-indolyl,
R13 für 1) Wasserstoff atom,R13 for 1) hydrogen atom,
2) -(C1-C4J-AIkYl1 2) - (C 1 -C 4 -alkyl ) 1
3) -(C0-C4)-Alkylen-C(O)-O-R14, 4) -(C0-C4)-Alkylen-C(O)-R14 oder3) - (C 0 -C 4 ) -alkylene-C (O) -O-R 14, 4) - (C 0 -C 4) -alkylene-C (O) -R 14 or
5) -(C0-C4)-Alkylen-O-R14 steht, und5) - (C 0 -C 4) alkylene-O-R 14, and
R14 für Wasserstoff atom, -(Ci-C4)-Alkyl, -NH2 oder -OH steht und R15 für Wasserstoffatom, -(Ci-C4)-Alkyl, -0-CF3, -NH2, -OH, -CF3 oderR 14 is hydrogen atom, - (C 1 -C 4) -alkyl, -NH 2 or -OH and R 15 is hydrogen, - (C 1 -C 4) -alkyl, -O-CF 3 , -NH 2, -OH, -CF 3 or
Halogen steht. Halogen is available.
6. Verwendung der Verbindung der Formel I gemäß der Ansprüche 2, 4 oder 5, wobei6. Use of the compound of formula I according to claims 2, 4 or 5, wherein
R1 für 1) Wasserstoffatom oder 2) -(C1-C^)-AIkYl, steht, R2 für 1) -(C1-C6)-Alkylen-NH2,R1 is 1) hydrogen atom or 2) - (C 1 -C ^) - -alkyl,, R 2 is 1) - (C 1 -C 6) alkylene-NH 2,
2) -(C1-C4)-Alkylen-Pyridyl-NH2,2) - (C 1 -C 4 ) -alkylene-pyridyl-NH 2 ,
3) -(Ci-C4)-Alkylen-Piperidinyl-NH2,3) - (C 1 -C 4) -alkylene-piperidinyl-NH 2,
4) -(C1-C4)-Alkylen-NH-C(=NH)-NH2,4) - (C 1 -C 4) alkylene-NH-C (= NH) -NH 2,
5) -(C1-C6)-Alkylen-NH-C(=NH)-(Ci-C4)-Alkyl, 6) -(C1-C4)-Alkylen-(C3-C6)-Cycloalkyl-NH2,5) - (C 1 -C 6) -alkylene-NH-C (= NH) - (Ci-C 4) -alkyl, 6) - (C 1 -C 4) alkylene- (C3-C6) cycloalkyl -NH 2 ,
7) -(C1-C4)-Alkylen-O-NH-C(=NH)-NH2,7) - (C 1 -C 4 ) -alkylene-O-NH-C (= NH) -NH 2,
8) -(C -i -C6)-Alkylen-N H-C(O)-O-(C -j -C4)-Alkylen-Phenyl,8) - (C 1 -C 6 ) -alkylene-N HC (O) -O- (C 1 -C 4 ) -alkylene-phenyl,
9) .(C 1 -C4)-Alkylen-N H-C(O)-(C 1 -C6)-Alkyl ,9). (C 1 -C 4 ) -alkylene-N HC (O) - (C 1 -C 6) -alkyl,
10) -(C1-C4)-Alkylen-Phenyl-NH2, 11) -(Ci-C4)-Alkylen-SO2-(C-i-C4)-Alkylen-NH2, oder10) - (C 1 -C 4) alkylene-phenyl-NH 2, 11) - (CiC 4) -alkylene-SO2- (CiC 4) alkylene-NH 2, or
12) -(C1-C4)-Alkylen-S-(C1-C4)-Alkylen-NH2, steht,12) - (C 1 -C 4 ) -alkylene-S- (C 1 -C 4 ) -alkylene-NH 2 ,
R3 für 1) -(C-|-C4)-Alkyl,R 3 is 1) - (C 1 -C 4 ) -alkyl,
2) -(C1-C4)-Alkylen-(C3-C6)-Cycloalkyl,2) - (C 1 -C 4 ) -alkylene- (C 3 -C 6 ) -cycloalkyl,
3) -(C-(-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch - OH substituiert ist,3) - (C - (- C 4 ) alkylene-phenyl, wherein phenyl is unsubstituted or substituted by - OH,
4) -(C1-C6)-Alkylen-NH-C(O)-O-(Ci-C4)-Alkylen-Phenyl,4) - (C 1 -C 6 ) -alkylene-NH-C (O) -O- (C 1 -C 4 ) -alkylene-phenyl,
5) Wasserstoffatom steht, R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander für 1) Wasserstoffatom,5) hydrogen, R4 is -N (R6) 2 , where R6 are identical or different and independently of one another represent 1) hydrogen atom,
2) -(C^C^-Alkyl,2) - (C 1 -C 4) -alkyl,
3) -(Crj-C4)-Alkylen-(C3-C8)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclopropyl, Adamantanyl, 1 ,7,7- Trimethyl-bicyclo[3.1.1]heptanyl, Tetrahydro-naphthalenyl, Decahydro- naphthalenyl, Octahydro-4,7-methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch -(Ci-C4)-Alkyl oder Phenyl substituiert ist,3) - (Crj-C4) -alkylene- (C3-C8) -cycloalkyl, wherein cycloalkyl is selected from the group consisting cyclohexyl, cyclopentyl, cyclopropyl, adamantanyl, 1, 7,7-trimethyl-bicyclo [3.1.1] heptanyl , Tetrahydro-naphthalenyl, decahydro- naphthalenyl, octahydro-4,7-methanoindenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently of one another mono-, di- or trisubstituted by - (C 1 -C 4) -alkyl or phenyl,
4) -C(R11)(R12)-Adamantanyl, 5) -CH(RI 1)-C(O)-NH-CH(R12)-R13,4) -C (R11) (R12) -adamantanyl, 5) -CH (RI 1) -C (O) -NH-CH (R 12) -R 13,
6) -(Crj-C^-Alkylen-Het, wobei Het ausgewählt ist aus der Gruppe6) - (Crj-C ^ -alkylene-Het, wherein Het is selected from the group
Benzimidazolyl, Isoxazolyl, Piperidinyl, Pyridinyl, Pyrrolidinyl, Thiophenyl und Benzo[1 ,3]dioxolyl,Benzimidazolyl, isoxazolyl, piperidinyl, pyridinyl, pyrrolidinyl, thiophenyl and benzo [1,3] dioxolyl,
7) 1 ,2,3,4-Tetrahydro-naphthalenyl, 8) -(Cn-C4)-Alkylen-C(R11 )(R12)-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch Phenyl oder Fluor substituiert ist,7) 1, 2,3,4-tetrahydro-naphthalenyl, 8) - (Cn-C4) -alkylene-C (R11) (R12) -phenyl, wherein phenyl is unsubstituted or independently mono-, di- or trisubstituted by phenyl or fluorine is substituted,
9) -CH(RH)-C(O)-NH2,9) -CH (RH) -C (O) -NH 2 ,
10) -CH(RI 1)-C(O)-NH-CH(R12)-CH2-OH, 11) -(C-|-Cg)-Alkylen-Phenyl, wobei Phenyl oder Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Chlor, Fluor, -C(O)-O-RH , -(Ci-C4)-Alkyl-O-R11 , -O-(C<|-C4)-Alkyl, Phenyl oder -(C-|-C4)-Alkyl substituiert sind, 12) -CH(RI 1)-C(O)-NH-(C<|-C4)-Alkyl, 13) -(Crj-C4)-Alkylen-C(R11 )(R12)-Bicyclo[3.1.1 ]heptanyl, wobei10) -CH (RI 1) -C (O) -NH-CH (R 12) -CH 2 -OH, 11) - (C 1 -C 6) -alkylene-phenyl, where phenyl or alkylene are unsubstituted or independently of one another or two times by chlorine, fluorine, -C (O) -O-RH, - (Ci-C4) -alkyl-O-R11, -O- (C < | -C4) alkyl, phenyl or - (C | C4) alkyl substituted, 12) -CH (RI 1) -C (O) -NH- (C <| -C4) -alkyl, 13) - (Crj-C4) -alkylene-C (R11) ( R12) bicyclo [3.1.1] heptanyl, wherein
Bicyclo[3.1.1]heptanyl unsubstituiert oder ein- bis vierfach durch -(Ci-C4)-Alkyl substituiert ist,Bicyclo [3.1.1] heptanyl is unsubstituted or substituted one to four times by - (C 1 -C 4) -alkyl,
14) -(C<|-C6)-Alkylen-C(O)-O-R11 , wobei Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Chlor, Fluor, -C(O)-O-RH , -(C-|-C4)-Alkyl-O-R11 , -O-(C-|-C4)-Alkyl, Phenyl oder14) - (C <| - C6) -alkylene-C (O) -O-R11, wherein alkylene is unsubstituted or independently of one another by chlorine, fluorine, -C (O) -O-RH, - (C - | -C4) alkyl-O-R11, -O- (C- | -C4) alkyl, phenyl or
-(Ci-C4)-Alkyl substituiert ist,- (C 1 -C 4) -alkyl is substituted,
15) -(C0-C4)-Alkylen-C(R11 )(R12)-C(O)-O-R11 , oder15) - (C 0 -C 4 ) -alkylene-C (R 11) (R 12) -C (O) -O-R 11, or
16) -CH2-CF2-CF3, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom an das sie gebunden sind einen Mono- oder Bicyclischen Ring bilden, ausgewählt aus der Gruppe Pyrrolidine, 2-aza-bicyclo[3.2.2]nonan und 7-aza-bicyclo[2.2.1]heptan, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(C-|-C4)-Alkyl,16) -CH 2 -CF 2 -CF 3 , or the two radicals R6 together with the N-atom to which they are attached form a mono- or bicyclic ring selected from the group Pyrrolidines, 2-aza-bicyclo [3.2.2] nonane and 7-aza-bicyclo [2.2.1] heptane, the ring being unsubstituted or mono- or disubstituted by - (C 1 -C 4) -alkyl,
-C(O)-O-R11 , -(C-|-C4)-Alkyl-O-R11 oder Phenyl substituiert ist, R7 für Wasserstoffatom oder -(C<|-C4)-Alkyl steht, R9 für Wasserstoffatom oder -(C <| -C4)-Alkyl steht,-C (O) -O-R11, - (C-C4) -alkyl-O-R11 or phenyl, R7 is hydrogen or - (C <| -C4) -alkyl, R9 is hydrogen or (C 1 -C 4) -alkyl,
R11 und R12 gleich oder verschieden sind und unabhängig voneinander fürR11 and R12 are the same or different and independently of each other
1 ) Wasserstoffatom ,1) hydrogen atom,
2) -(C-i-C^-Alkyl,2) - (C 1 -C 4) -alkyl,
3) -(Crj-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch -OH, Halogen oder3) - (Crj-C4) alkylene-phenyl, wherein phenyl unsubstituted or independently of one another once, twice or three times by -OH, halogen or
-O-(C-|-C4)-Alkyl substituiert ist,-O- (C 1 -C 4) -alkyl is substituted,
4) -(Crj-C4)-Alkylen-(C3-C-|2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adamantanyl, 1 ,7,7-Trimethyl-bicyclo[3.1.1]heptanyl, Octahydro-4,7-methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch -(Ci-C4)-Alkyl, -C(O)-O-RI 3 oder Phenyl substituiert ist, oder4) - (Crj-C4) -alkylene- (C3-C- | 2) -cycloalkyl, wherein cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, 1, 7,7-trimethyl-bicyclo [3.1 .1] heptanyl, octahydro-4,7-methano-indenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently of one another once, twice, three or four times by - (C 1 -C 4) -alkyl, C (O) -O-RI 3 or phenyl, or
5) -(Crj-C4)-Alkylen-Indolyl, stehen,5) - (Crj-C4) -alkylene-indolyl,
R13 für 1) Wasserstoff atom, 2) -(C1-C4)-Alkyl,R13 represents 1) hydrogen atom, 2) - (C 1 -C 4 ) -alkyl,
3) -(C0-C4)-Alkylen-C(O)-O-R14,3) - (C 0 -C 4 ) -alkylene-C (O) -O-R 14,
4) -(Cn-C4)-Alkylen-C(O)-R14 oder4) - (Cn-C4) -alkylene-C (O) -R 14 or
5) -(Cn-C4)-Alkylen-O-R 14 steht,5) - (Cn-C4) -alkylene-O-R 14,
R14 für Wasserstoffatom, -(C<|-C4)-Alkyl, -NH2 oder -OH steht und R15 für Wasserstoffatom, -(C 1 -C^)-Al ky I, -0-CF3, -NH2, -OH, -CF3 oderR 14 is hydrogen, - (C 1 -C 4) -alkyl, -NH 2 or -OH and R 15 is hydrogen, - (C 1 -C 4) -alkyl, -O-CF 3 , -NH 2, -OH , -CF3 or
Halogen steht.Halogen is available.
7. Verwendung der Verbindung der Formel I gemäß Anspruch 3, wobei7. Use of the compound of formula I according to claim 3, wherein
R1 für 1) Wasserstoffatom oder 2) -(C-|-C4)-Alkyl, steht, R2 für 1) -(C1-C6)-Alkylen-NH2,R 1 represents 1) hydrogen or 2) - (C 1 -C 4) -alkyl, R 2 for 1) - (C 1 -C 6 ) -alkylene-NH 2,
2) -(C0-C4)-Alkylen-Pyridyl-NH2,2) - (C 0 -C 4) -alkylene-pyridyl-NH 2 ,
3) -(Co-C4)-Alkylen-Piperidinyl-NH2,3) - (Co-C4) -alkylene-piperidinyl-NH2,
4) -(C0-C4)-Alkylen-Thiazolyl-NH2, 5) -(C1-C6)-Alkylen-NH-C(=NH)-NH2,4) - (C 0 -C 4 ) -alkylene-thiazolyl-NH 2 , 5) - (C 1 -C 6) -alkylene-NH-C (= NH) -NH 2 ,
6) -(C0-C4)-Alkylen-(C3-C8)-Cycloalkyl-NH2,6) - (C 0 -C 4) -alkylene- (C 3 -C 8 ) -cycloalkyl-NH 2 ,
7) -(C1-C6)-Alkylen-NH-C(=NH)-(C-|-C4)-Alkyl,7) - (C 1 -C 6) -alkylene-NH-C (= NH) - (C 1 -C 4) -alkyl,
8) -(C0-C4)-Alkylen-O-NH-C(=NH)-NH2j 8) - (C 0 -C 4) alkylene-O-NH-C (= NH) -NH 2j
9) -(C1 -Ce)-Alkylen-N H-C(O)-O-(C -i -C4)-Alkylen-Aryl, wobei Aryl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist,9) - (C 1 -Ce) alkylene-N HC (O) -O- (C -i -C4) alkylene-aryl, wherein aryl is unsubstituted or substituted by -NH 2 or -NH 2, and mono- , is substituted two or three times by R 15,
10) -(C0-C4)-Alkylen-NH-C(O)-(C1-C4)-Alkyl,10) - (C 0 -C 4 ) -alkylene-NH-C (O) - (C 1 -C 4 ) -alkyl,
11) -(Co-C4)-Alkylen-(C6-C-|4)-Aryl, wobei Aryl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist, oder11) - ((Co-C4) -alkylene- C6-C | 4) -aryl, wherein aryl is unsubstituted or substituted by -NH 2 or -NH 2, and mono-, di- or trisubstituted by R15, or
12) -(C<|-C4)-Alkylen-SOx-(Ci-C4)-Alkylen-NH2 worin x die ganze12) - (C <| - C4) -alkylene-SO x - (Ci-C4) -alkylene-NH 2 wherein x is the whole
Zahl Null, 1 oder 2 bedeutet, steht, R3 für 1) -(Ci-C4)-Alkyl,Number zero, 1 or 2, R 3 is 1) - (C 1 -C 4 ) -alkyl,
2) -(C0-C4)-Alkylen-(C3-C8)-Cycloalkyl, 3) -(Ci-CßJ-Alkylen-Aryl, wobei Aryl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,2) - (C 0 -C 4) -alkylene- (C 3 -C 8) -cycloalkyl, 3) - (C 1 -C 6 -alkyl-aryl, where aryl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15,
4) -(C1-C6)-Alkylen-NH-C(O)-O-(Ci-C4)-Alkylen-Aryl, wobei Aryl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist, 5) -(C-i-C^-Alkylen-NH-PG,4) - (C 1 -C 6) -alkylene-NH-C (O) -O- (C 1 -C 4 ) -alkylene-aryl, where aryl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15, 5) - (CiC ^ alkylene-NH-PG,
6) -(C-|-C6)-Alkylen-O-PG,6) - (C 1 -C 6 ) -alkylene-O-PG,
7) -(C-|-C6)-Alkyl, oder7) - (C 1 -C 6 ) -alkyl, or
8) Wasserstoffatom, steht, wobei PG für t-Butyl-, t-Butyloxycarbonyl oder Benzyloxycarbonyl steht, R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander für8) hydrogen, where PG is t-butyl, t-butyloxycarbonyl or benzyloxycarbonyl, R4 is -N (R6) 2, wherein R6 are the same or different and independently of one another
1 ) Wasserstoff atom ,1) hydrogen atom,
2) -(C1-Ce)-AIkYl, 3) -(Co-C4)-Alkylen-(C3-C-|2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R11 , Halogen, -C(O)-O-RH , -(Ci-C4)-Alkyl-O-R11 oder -O-(C-|-C4)-Alkyl substituiert ist,2) - (C 1 -C 6) alkyl, 3) - (C 0 -C 4) alkylene- (C 3 -C 12) -cycloalkyl, where cycloalkyl is unsubstituted or independently of one, two, three or four times through R11, halogen, -C (O) -O-H, - (Ci-C 4) -alkyl-O-R11 or -O- (C- | -C4) substituted alkyl,
4) -(Co-C4)-Alkylen-C(R11)(R12)-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch4) - (Co-C4) -alkylene-C (R11) (R12) - (C3-Ci2) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently mono-, di- or trihydric
R11 , Halogen, -C(O)-O-RH , -(C-i-C^-Alkyl-O-RH oder -0-(C1 -C4)-Alkyl substituiert ist,R 11, halogen, -C (O) -O-RH, - (C 1 -C 4 -alkyl-O-RH or -O- (C 1 -C 4 ) -alkyl,
5) -(Co-C4)-Alkylen-Het, wobei unter Het ein 4- bis 15-gliedriges heterocyclisches Ringsystem verstanden wird mit 4 bis 15 Ringatomen, die in ein, zwei oder drei miteinander verbundenen Ringsystemen vorliegen und die ein, zwei, drei oder vier gleiche oder verschiedene Heteroatome aus der Reihe Sauerstoff, Stickstoff oder Schwefel enthalten, wobei Het oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-RH , -(C-] -C4)-Alkyl-O-R11 oder -0-(C1 -C4)-Alkyl substituiert sind,5) - (Co-C4) -alkylene-Het, where Het is a 4- to 15-membered heterocyclic ring system is understood with 4 to 15 ring atoms, which are present in one, two or three interconnected ring systems and the one, two, contain three or four identical or different heteroatoms from the series oxygen, nitrogen or sulfur, wherein Het or alkylene is unsubstituted or independently of one another once, twice or three times by R11, halogen, -C (O) -O-RH, - (C -] -C 4) -alkyl-O-R 11 or -O- (C 1 -C 4) -alkyl,
6) -(Crj-C6)-Alkylen-Aryl, wobei Aryl oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-R11 , -(Crj-C4)-Alkyl-O-R11 oder -O-(C<|-C4)-Alkyl substituiert sind,6) - (Crj-C6) -alkylene-aryl, where aryl or alkylene are unsubstituted or independently of one another mono-, di- or trisubstituted by R11, halogen, -C (O) -O-R11, - (Crj-C4) - Alkyl-O-R11 or -O- (C <| - C4) -alkyl,
7) -(C0-C4)-Alkylen-C(R11 )(R12)-Aryl, wobei Aryl oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch7) - (C 0 -C 4 ) -alkylene-C (R 11) (R 12) -aryl, wherein aryl or alkylene is unsubstituted or independently mono-, di- or trihydric
R11 , Halogen, -C(O)-O-RH , -(Cn-C4)-Alkyl-O-R11 oder -0-(C1 -C4)-Alkyl substituiert sind,R11, halogen, -C (O) -O-H, - (Cn-C4) -alkyl-O-R11 or -0- (C 1 -C 4) alkyl substituted,
8) 1 ,2,3,4-Tetrahydro-naphthalenyl,8) 1, 2,3,4-tetrahydro-naphthalenyl,
9) -(Co-C4)-Alkylen-CH(RH)-C(O)-NH2, 10) -(C0-C4)-Alkylen-CH(R11)-C(O)-NH-(Ci-C4)-Alkyl, 11 ) -(Co-C4)-Alkylen-CH(R11 )-C(0)-NH-CH(R12)-R13,9) - (Co-C 4 ) -alkylene-CH (RH) -C (O) -NH 2 , 10) - (C 0 -C 4) -alkylene-CH (R 11) -C (O) -NH- ( C 1 -C 4 ) -alkyl, 11) - (Co-C4) -alkylene-CH (R11) -C (O) -NH-CH (R12) -R13,
12) -(Co-C6)-Alkylen-C(0)-O-R11 , wobei Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch R11 , Halogen, -C(O)-O-RH , -(C<|-C4)-Alkyl-O-R11 oder -O-(C<|-C4)-Alkyl substituiert ist, 13) -(Co-C4)-Alkylen-C(R11)(R12)-C(O)-O-R11 , oder12) - (Co-C6) -alkylene-C (O) -O-R11, wherein alkyls are unsubstituted or independently of one another once or twice by R11, halogen, -C (O) -O-RH, - (C <| -C 4) -alkyl-O-R 11 or -O- (C 1 -C 4) -alkyl, 13) - (C 1 -C 4 ) -alkylene-C (R 11) (R 12) -C (O) - O-R11, or
14) -(C-|-C3)-Fluoralkyl, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom, an das sie gebunden sind, einen mono- oder bicyclischen Ring mit 4 bis 9 Ringatomen bilden, der gesättigt, teilweise gesättigt oder aromatisch ist, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(C-|-C4)-Alkyl, -C(O)-O-R11 ,14) - (C 1 -C 3) -fluoroalkyl, or the two R 6 together with the N-atom to which they are attached form a mono- or bicyclic ring having 4 to 9 ring atoms, which is saturated, in part is saturated or aromatic, the ring being unsubstituted or mono- or disubstituted by - (C- | -C4) alkyl, -C (O) -O-R11,
Halogen, -(C-|-C4)-Alkyl-O-R11 oder Phenyl substituiert ist, R7 für Wasserstoffatom oder -(C-|-C4)-Alkyl steht, R9 für Wasserstoffatom oder -(Ci-C4)-Alkyl steht,Is halogen, - (C 1 -C 4) -alkyl-O-R 11 or phenyl, R 7 is hydrogen or - (C 1 -C 4) -alkyl, R 9 is hydrogen or - (C 1 -C 4) -alkyl .
R11 und R12 gleich oder verschieden sind und unabhängig voneinander für 1) Wasserstoffatom,R 11 and R 12 are identical or different and independently of one another represent 1) hydrogen atom,
2) -(Ci-C4)-Alkyl,2) - (C 1 -C 4 ) -alkyl,
3) -(Crj-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch Halogen, -OH oder -O-(C-|-C4)-Alkyl substituiert ist, 4) -(Co-C4)-Alkylen-(C3-C<i2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R13, Halogen, -C(O)-O-RI 3, -(Ci-C4)-Alkyl-O-R13, -O-(Ci-C4)-Alkyl oder3) - (Cr j-C4) alkylene-phenyl, where phenyl is unsubstituted or substituted independently of one another, di- or trisubstituted by halogen, -OH or -O- (C- | -C4) alkyl is substituted, 4) - (Co-C4) -alkylene- (C3-C < i2) -cycloalkyl, where cycloalkyl is unsubstituted or independently of one another once, twice, three or four times by R13, halogen, -C (O) -O-RI 3 , (C 1 -C 4 ) -alkyl-O-R 13, -O- (C 1 -C 4 ) -alkyl or
-(Crj-C4)-Alkylen-Phenyl substituiert ist, 5) -(C0-C4)-Alkylen-C(O)-N(R13)2 oder 6) -(Crj-C4)-Alkylen-Indolyl, stehen,(C 1 -C 4 ) -alkylene-phenyl, 5) - (C 0 -C 4 ) -alkylene-C (O) -N (R 13) 2 or 6) - (C 1 -C 4 ) -alkylene-indolyl, stand,
R13 für 1 ) Wasserstoffatom,R 13 is 1) hydrogen,
2) -(C-i-C^-Alkyl,2) - (C 1 -C 4) -alkyl,
3) -(C0-C4)-Alkylen-C(O)-O-R14,3) - (C 0 -C 4 ) -alkylene-C (O) -O-R 14,
4) -(Crj-C4)-Alkylen-C(O)-R14 oder 5) -(C0-C4)-Alkylen-O-R14 steht,4) - (Crj-C4) -alkylene-C (O) -R14 or 5) - (C 0 -C 4 ) -alkylene-O-R 14,
R14 für Wasserstoff atom, -(C-i-C^-Alkyl, -NH2 oder -OH, steht und R15 für Wasserstoffatom, -(C<|-C4)-Alkyl, -0-CF3, -NH2, -OH, -CF3 oderR14 represents hydrogen atom, - (C 1 -C 4 -alkyl, -NH 2 or -OH, and R 15 represents hydrogen atom, - (C 1 -C 4 ) -alkyl, -O-CF 3 , -NH 2, -OH, -CF 3 or
Halogen steht.Halogen is available.
8. Verwendung der Verbindung der Formel I gemäß Anspruch 3 oder 7, wobei R1 für 1) Wasserstoffatom oder8. Use of the compound of formula I according to claim 3 or 7, wherein R 1 is hydrogen or
2) -(C1 -C4)-Alkyl, steht,2) - (C 1 -C 4 ) -alkyl,
R2 für 1) -(C1-C6)-Alkylen-NH2, 2) -(C1-C4)-Alkylen-Pyridyl-NH2,R 2 for 1) - (C 1 -C 6 ) -alkylene-NH 2 , 2) - (C 1 -C 4 ) -alkylene-pyridyl-NH 2 ,
3) -(Ci-C4)-Alkylen-Piperidinyl-NH2,3) - (C 1 -C 4 ) -alkylene-piperidinyl-NH 2,
4) -(C1-C6)-Alkylen-NH-C(=NH)-NH2,4) - (C 1 -C 6 ) -alkylene-NH-C (= NH) -NH 2 ,
5) -(C0-C4)-Alkylen-(C3-C6)-Cycloalkyl-NH2,5) - (C 0 -C 4 ) -alkylene- (C 3 -C 6 ) -cycloalkyl-NH 2 ,
6) -(Ci-C6)-Alkylen-NH-C(=NH)-(Ci-C4)-Alkyl, 7) -(C1-C4)-Alkylen-O-NH-C(=NH)-NH2i 6) - (Ci-C6) alkylene-NH-C (= NH) - (Ci-C 4) -alkyl, 7) - (C 1 -C 4) -alkylene-O-NH-C (= NH) -NH 2i
8) -(C1-C6)-Alkylen-NH-C(O)-O-(C-|-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist,8) - (C 1 -C 6) -alkylene-NH-C (O) O- (C- | -C4) alkylene-phenyl, where phenyl is unsubstituted or substituted by -NH 2 or -NH 2, and is monosubstituted, disubstituted or trisubstituted by R 15,
9) -(C1 -C4)-Alkylen-N H-C(O)-(C -i-C6)-Alkyl, 10) -(C1-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch -9) - (C 1 -C 4 ) -alkylene-N HC (O) - (C 1 -C 6 ) -alkyl, 10) - (C 1 -C 4 ) -alkylene-phenyl, where phenyl is unsubstituted or substituted by
NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durchNH 2 is substituted or by -NH 2 and one, two or three times by
R15 substituiert ist,R 15 is substituted,
11) -(C1-C4)-Alkylen-SO2-(Ci-C4)-Alkylen-NH2, oder11) - (C 1 -C 4 ) -alkylene-SO 2 - (C 1 -C 4 ) -alkylene-NH 2 , or
12) -(C1-C4)-Alkylen-S-(C1-C4)-Alkylen-NH2, steht, R3 für 1) -(C-i-C^-Alkyl,12) - (C 1 -C 4 ) -alkylene-S- (C 1 -C 4 ) -alkylene-NH 2 , R 3 is 1) - (C 1 -C 4 -alkyl)
2) -(C1 -C4)-Alkylen-(C3-C6)-Cycloalkyl,2) - (C 1 -C 4 ) -alkylene- (C 3 -C 6 ) -cycloalkyl,
3) -(C"|-C4)-Alkylen-Phenyl, wobei Phenyl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist, 4) -(Ci-C6)-Alkylen-NH-C(O)-O-(Ci-C4)-Alkylen-Phenyl, wobei Phenyl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,3) - (C 1 -C 4 ) -alkylene-phenyl, where phenyl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15, 4) - (C 1 -C 6) -alkylene-NH-C (O) -O- (C 1 -C 4) -alkylene-phenyl, where phenyl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15,
5) Wasserstoffatom steht, R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander für5) is hydrogen, R4 is -N (R6) 2, where R6 are the same or different and independently of one another
1) Wasserstoffatom,1) hydrogen atom,
2) -(C1-C4)-Alkyl,2) - (C 1 -C 4 ) -alkyl,
3) -(Co-C4)-Alkylen-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adaman- tanyl, Bicyclo[3.1.1]heptanyl, Decahydro-naphthalenyl, Tetrahydronaph-thalenyl, Octahydro-4,7-methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach substituiert ist durch -(Ci-C4)-Alkyl, -C(O)-O-RH oder -(C-|-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch Halogen substituiert ist,3) - (C 1 -C 4) -alkylene- (C 3 -C 12) -cycloalkyl, where cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, bicyclo [3.1.1] heptanyl, decahydro-naphthalenyl, Tetrahydronaphthalene, octahydro-4,7-methanoindenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently of one another mono-, di-, tri- or tetra-substituted by - (C 1 -C 4) -alkyl, -C (O) -O-RH or - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or substituted by halogen,
4) -(Co-C4)-Alkylen-C(R11)(R12)-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adamantanyl, Bicyclo[3.1.1]heptanyl, Decahydro-naphthalenyl, Tetrahydronaphthalenyl, Octahydro-4,7-methano-indenyl oder4) - (Co-C 4 ) -alkylene-C (R 11) (R 12) - (C 3 -C 12) -cycloalkyl, where cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, bicyclo [3.1.1 ] heptanyl, decahydro-naphthalenyl, tetrahydronaphthalenyl, octahydro-4,7-methano-indenyl or
Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach substituiert ist durch -(Ci-C4)-Alkyl, -C(O)-O-RH oder -(C«|-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch Halogen substituiert ist, 5) -(Co-C4)-Alkylen-Het, wobei Het ausgewählt ist aus der Gruppe Acridinyl,Bicyclo [2.2.1] heptanyl and wherein cycloalkyl is unsubstituted or substituted independently of one another, di-, tri- or four times substituted by - (Ci-C4) alkyl, -C (O) -O-H or - (C " C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or substituted by halogen, 5) - (C 1 -C 4) -alkylene-Het, where Het is selected from the group acridinyl,
Azepinyl, Azetidinyl, Aziridinyl, Benzimidazalinyl, Benzimidazolyl, Benzo[1 ,3]dioxolyl, Benzofuranyl, Benzothiofuranyl, Benzothiophenyl, Benzoxazolyl, Benzthiazolyl, Benztriazolyl, Benztetrazolyl, Benzisoxazolyl, Benzisothiazolyl, Carbazolyl, 4aH-Carbazolyl, Carbolinyl, Chinazolinyl, Chinolinyl, 4H-Chinolizinyl, Chinoxalinyl, Chinuclidinyl, Chromanyl, Chromenyl,Azepinyl, azetidinyl, aziridinyl, benzimidazalinyl, benzimidazolyl, benzo [1,3] dioxolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H- Quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl,
Cinnolinyl, Deca-hydrochinolinyl, Dibenzofuranyl, Dibenzothiophenyl, Dihydrofuran[2,3-b]-tetrahydrofuranyl, Dihydrofuranyl, Dioxolyl, Dioxanyl, 2H, 6H-1 ,5,2-Dithiazinyl, Furanyl, Furazanyl, Imidazolidinyl, Imidazolinyl, Imidazolyl, 1 H-lndazolyl, Indolinyl, Indolizinyl, Indolyl, 3H-lndolyl, Isobenzofuranyl, Isochromanyl, Isoindazolyl, Isoindolinyl, Isoindolyl, Isochinolinyl (Benzimidazolyl), Isothiazolidinyl, 2-lsothiazolinyl, Isothiazolyl, Isoxazolyl,Cinnolinyl, deca-hydroquinolinyl, dibenzofuranyl, dibenzothiophenyl, Dihydrofuran [2,3-b] tetrahydrofuranyl, dihydrofuranyl, dioxolyl, dioxanyl, 2H, 6H-1,2,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolidinyl, 2-isothiazolinyl, isothiazolyl, isoxazolyl,
Isoxazolidinyl, 2-lsoxazolinyl, Morpholinyl, Naphthyridinyl, Octahydroisochinolinyl, Oxadiazolyl, 1 ,2,3-Oxadiazolyl, 1 ,2,4-Oxadiazolyl, 1 ,2,5- Oxadiazolyl, 1 ,3,4-Oxadiazolyl, Oxazolidinyl, Oxazolyl, Oxazolidinyl, Oxothiolanyl, Pyrimidinyl, Phenanthridinyl, Phenanthrolinyl, Phenazinyl, Phenothiazinyl, Phenoxathiinyl, Phenoxazinyl, Phthalazinyl, Piperazinyl,Isoxazolidinyl, 2-isoxazolinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1, 2,3-oxadiazolyl, 1, 2,4-oxadiazolyl, 1, 2,5-oxadiazolyl, 1, 3,4-oxadiazolyl, oxazolidinyl, oxazolyl, Oxazolidinyl, oxothiolanyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,
Piperidinyl, Pteridinyl, Purynyl, Pyranyl, Pyrazinyl, Pyroazolidinyl, Pyrazolinyl, Pyrazolyl, Pyridazinyl, Pryidooxazolyl, Pyridoimidazolyl, Pyridothiazolyl, Pyridothiophenyl, Pyridinyl, Pyridyl, Pyrimidinyl, Pyrrolidinyl, Pyrrolinyl, 2H- Pyrrolyl, Pyrrolyl, Tetrahydrofuranyl, Tetrahydroisochinolinyl, Tetrahydrochinolinyl, Tetrahydropyridinyl, 6H-1 ,2,5-Thiadazinyl, 1 ,2,3-Piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl, 6H-1, 2,5-thiadazinyl, 1, 2,3-
Thiadiazolyl, 1 ,2,4-Thiadiazolyl, 1 ,2,5-Thiadiazolyl, 1 ,3,4-Thiadiazolyl, Thianthrenyl, Thiazolyl, Thienyl, Thienoimidazolyl, Thienooxazolyl, Thienopyridin, Thienothiazolyl, Thiomorpholinyl, Thiophenyl, Triazinyl, 1 ,2,3- Triazolyl, 1 ,2,3-Triazolyl, 1 ,2,4-Triazolyl, 1 ,2,5-Triazolyl, 1 ,3,4-Triazolyl und Xanthenyl, wobei Het oder Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch -(C-f -C4)-Alkyl substituiert istThiadiazolyl, 1, 2,4-thiadiazolyl, 1, 2,5-thiadiazolyl, 1, 3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienoimidazolyl, thienooxazolyl, thienopyridine, thienothiazolyl, thiomorpholinyl, thiophenyl, triazinyl, 1, 2, 3-triazolyl, 1, 2,3-triazolyl, 1, 2,4-triazolyl, 1, 2,5-triazolyl, 1, 3,4-triazolyl and xanthenyl, wherein Het or alkylene unsubstituted or independently of one another once or twice is substituted by - (Cf -C4) -alkyl
6) -(Ci-C6)-Alkylen-Phenyl, wobei Phenyl oder Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Halogen, Phenyl, -C(O)-O-RH , -(C1 -C4)-Alkyl-O-R11 , -O-(C<|-C4)-Alkyl oder -(Ci-C4)-Alkyl substituiert sind,6) - (C 1 -C 6) -alkylene-phenyl, where phenyl or alkylene is unsubstituted or independently of one another by halogen, phenyl, -C (O) -O-RH, - (C 1 -C 4) -alkyl- O-R11, -O- (C < | - C4) -alkyl or - (Ci-C4) -alkyl are substituted,
7) -(Co-C4)-Alkylen-C(R11 )(R12)-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch Phenyl oder Fluor substituiert ist,7) - (Co-C4) -alkylene-C (R11) (R12) -phenyl, where phenyl is unsubstituted or independently of one another mono-, di- or trisubstituted by phenyl or fluorine,
8) 1 ,2,3,4-Tetrahydro-naphthalenyl, 9) -(C0-C4)-Alkylen-CH(R11)-C(O)-NH2,8) 1, 2,3,4-tetrahydro-naphthalenyl, 9) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH 2 ,
10) -(C0-C4)-Alkylen-CH(R11)-C(O)-NH-(C<|-C4)-Alkyl, 11 ) -(Co-C4)-Alkylen-CH(R11 )-C(O)-NH-CH(R12)-R13,10) - (C 0 -C 4) alkylene-CH (R11) -C (O) -NH- (C <| -C4) alkyl, 11) - (Co-C 4 ) -alkylene-CH (R 11) -C (O) -NH-CH (R 12) -R 13,
12) -(Ci-C6)-Alkylen-C(O)-O-R11 , wobei Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Halogen, Phenyl, -C(O)-O-RH , -(C-|-C4)-Alkyl-O-R11 , -O-(C<|-C4)-Alkyl oder -(C<|-C4)-Alkyl substituiert ist,12) - (C 1 -C 6) -alkylene-C (O) -O-R 11, where alkylene is unsubstituted or independently of one another by halogen, phenyl, -C (O) -O-RH, - (C- | -C 4 ) -alkyl-O-R 11, -O- (C 1 -C 4 ) -alkyl or - (C 1 -C 4 ) -alkyl,
13) -(Co-C4)-Alkylen-C(R11 )(R12)-C(O)-O-R11 , oder13) - (Co-C 4) -alkylene-C (R11) (R12) -C (O) -O-R11, or
14) -(C-|-C3)-Fluoralkyl, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom an das sie gebunden sind einen Mono- oder Bicyclischen Ring bilden ausgewählt aus der Gruppe Pyrrolidin, Piperidin, 2-Aza-bicyclo[3.2.2]nonan und 7-Aza-bicyclo[2.2.1]hep-tan, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(Ci-C4)-Alkyl, -14) - (C 1 -C 3) -fluoroalkyl, or the two radicals R 6 together with the N-atom to which they are attached form a mono- or bicyclic ring selected from the group pyrrolidine, piperidine, 2-aza bicyclo [3.2.2] nonane and 7-azabicyclo [2.2.1] hep-tane, the ring being unsubstituted or mono- or disubstituted by - (C 1 -C 4 ) -alkyl,
C(O)-O-RH , -(C1 -C4)-Alkyl-O-R11 oder Phenyl substituiert ist, R7 für Wasserstoff atom oder -(Ci-C4)-Alkyl steht, R9 für Wasserstoffatom oder -(C-j-C4)-Alkyl steht, R11 und R12 gleich oder verschieden sind und unabhängig voneinander fürC (O) -O-H, - (C 1 -C 4) -alkyl-O-R11 or phenyl, R7 is hydrogen atom or - (Ci-C4) -alkyl, R9 is hydrogen atom or - ( CjC 4 ) alkyl, R11 and R12 are the same or different and are each independently
1) Wasserstoffatom,1) hydrogen atom,
2) -(C -i-C/O-Alkyl,2) - (C 1 -C 4) -alkyl,
3) -(Crj-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch -OH, Halogen oder -O-(Ci-C4)-Alkyl substituiert ist,3) - (Cr j -C 4) -alkylene-phenyl, wherein phenyl is unsubstituted or substituted independently of one another, two or three times by -OH, halogen or -O- (Ci-C4) alkyl is substituted,
4) -(Co-C4)-Alky!en-(C3-C<|2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adamantanyl, Bicyclo[3.1.1]heptanyl, Octahydro-4,7-methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch -(C-|-C4)-Alkyl,4) - (Co-C 4 ) -Alky! En- (C 3 -C < 2) -cycloalkyl, where cycloalkyl is selected from the group of cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, bicyclo [3.1.1] heptanyl, Octahydro-4,7-methanoindenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently of one another mono-, di-, tri- or tetra-substituted by - (C 1 -C 4 ) -alkyl,
-C(O)-O-RI 3 oder Phenyl substituiert ist, oder-C (O) -O-RI 3 or phenyl, or
5) -(Crj-C4)-Alkylen-lndolyl, stehen,5) - (Crj-C 4 ) -alkylene-indolyl,
R13 für 1) Wasserstoffatom, 2) -(C^C^-Alkyl, 3) -(C0-C4)-Alkylen-C(O)-O-R14, 4) -(C0-C4)-Alkylen-C(O)-R14 oderR13 represents 1) hydrogen, 2) - (C 1 -C 4 -alkyl, 3) - (C 0 -C 4 ) -alkylene-C (O) -O-R 14, 4) - (C 0 -C 4 ) -alkylene-C (O) -R 14 or
5) -(Co-C4)-Alkylen-0-R14 steht, und5) - (Co-C4) -alkylene-0-R14, and
R14 für Wasserstoffatom, -(Ci-C4)-Alkyl, -NH2 oder -OH steht undR 14 is hydrogen, - (C 1 -C 4 ) -alkyl, -NH 2 or -OH and
R15 für Wasserstoffatom, -(C<j-C4)-Alkyl, -O-CF3, -NH2, -OH1 -CF3 oder Halogen steht.R 15 is hydrogen, - (C jC 4 ) alkyl, -O-CF 3, -NH 2, -OH 1 -CF 3 or halogen.
9. Verwendung der Verbindung der Formel I gemäß der Ansprüche 3, 7 oder 8, wobei9. Use of the compound of formula I according to claims 3, 7 or 8, wherein
R1 für 1) Wasserstoffatom oder 2) -(C -i-C4)-Alkyl, steht,R 1 represents 1) hydrogen or 2) - (C 1 -C 4 ) -alkyl,
R2 für 1) -(C1-C6)-Alkylen-NH2,R 2 for 1) - (C 1 -C 6) -alkylene-NH 2,
2) -(C1-C4)-Alkylen-Pyridyl-NH2,2) - (C 1 -C 4 ) -alkylene-pyridyl-NH 2 ,
3) -(C1 -C4)-Alkylen-Piperidinyl-NH2,3) - (C 1 -C 4 ) -alkylene-piperidinyl-NH 2,
4) -(C1-C4)-Alkylen-NH-C(=NH)-NH2, 5) -(C1-C6)-Alkylen-NH-C(=NH)-(Ci-C4)-Alkyl,4) - (C 1 -C 4 ) -alkylene-NH-C (= NH) -NH 2 , 5) - (C 1 -C 6 ) -alkylene-NH-C (= NH) - (Ci-C 4 ) alkyl,
6) -(C1-C4)-Alkylen-(C3-C6)-Cycloalkyl-NH2,6) - (C 1 -C 4 ) -alkylene- (C 3 -C 6 ) -cycloalkyl-NH 2 ,
7) -(C1-C4)-Alkylen-O-NH-C(=NH)-NH2i 7) - (C 1 -C 4 ) alkylene-O-NH-C (= NH) -NH 2i
8) -(C-i-C6)-Alkylen-NH-C(O)-O-(Ci-C4)-Alkylen-Phenyl,8) - (C 1 -C 6 ) -alkylene-NH-C (O) -O- (C 1 -C 4 ) -alkylene-phenyl,
9) -(C-j-C4)-Alkylen-NH-C(O)-(C-|-C6)-Alkyl oder 10) -(C-i-C4)-Alkylen-Phenyl-NH2,9) - (C 1 -C 4 ) -alkylene-NH-C (O) - (C 1 -C 6) -alkyl or 10) - (C 1 -C 4 ) -alkylene-phenyl-NH 2 ,
11) -(Ci-C2)-Alkylen-SO2-(C1-C4)-Alkylen-NH2, oder11) - (C 1 -C 2 ) -alkylene-SO 2 - (C 1 -C 4 ) -alkylene-NH 2 , or
12) -(C1-C2)-Alkylen-S-(C1-C4)-Alkylen-NH2, steht, R3 für 1) -(C^C^-Alkyl,12) - (C 1 -C 2 ) -alkylene-S- (C 1 -C 4 ) -alkylene-NH 2, R 3 is 1) - (C 1 -C 4 ) -alkyl,
2) -(C1-C4)-Alkylen-(C3-C6)-Cycloalkyl, 3) -(C-|-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch -2) - (C 1 -C 4) alkylene- (C3-C6) -cycloalkyl, 3) - (C- | -C4) alkylene-phenyl, where phenyl is unsubstituted or substituted by -
OH substituiert ist,OH is substituted,
4) -(C1-C6)-Alkylen-NH-C(O)-O-(Ci-C4)-Alkylen-Phenyl,4) - (C 1 -C 6) -alkylene-NH-C (O) -O- (C 1 -C 4 ) -alkylene-phenyl,
5) Wasserstoffatom steht, R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander für5) hydrogen, R4 is -N (R6) 2 , wherein R6 are the same or different and independently of each other
1) Wasserstoffatom,1) hydrogen atom,
2) -(C1-Ce)-AIkYl,2) - (C 1 -Ce) -Alkyl,
3) -(Co-C4)-Alkylen-(C3-C8)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclopropyl, Adamantanyl, 1 ,7,7-3) - (Co-C4) -alkylene- (C3-C8) -cycloalkyl, where cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclopropyl, adamantanyl, 1, 7,7-
Trimethyl-bicyclo[3.1.1]heptanyl, Decahydro-naphthalenyl, Octahydro-4,7- methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch -(C-|-C4)-Alkyl oder Phenyl substituiert ist, 4) -C(R11)(R12)-Adamantanyl,Trimethyl-bicyclo [3.1.1] heptanyl, decahydro-naphthalenyl, octahydro-4,7-methanoindenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently mono-, di- or trisubstituted by - (C 1-6) C 1 -C 4) -alkyl or phenyl, 4) -C (R 11) (R 12) -adamantanyl,
5) -CH(R11)-C(O)-NH-CH(R12)-R13,5) -CH (R11) -C (O) -NH-CH (R12) -R13,
6) -(Crj-C4)-Alkylen-Het, wobei Het ausgewählt ist aus der Gruppe6) - (Crj-C4) -alkylene-Het, wherein Het is selected from the group
Benzimidazolyl, Isoxazolyl, Piperidinyl, Pyridyl, Pyrrolidinyl, Thiophenyl und Benzo[1 ,3]dioxolyl, 7) 1 ,2,3,4-Tetrahydro-naphthalenyl,Benzimidazolyl, isoxazolyl, piperidinyl, pyridyl, pyrrolidinyl, thiophenyl and benzo [1,3] dioxolyl, 7) 1,2,3,4-tetrahydro-naphthalenyl,
8) -(Co-C4)-Alkylen-C(R11 )(R12)-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch Phenyl oder Fluor substituiert ist,8) - (Co-C4) -alkylene-C (R11) (R12) -phenyl, where phenyl is unsubstituted or independently of one another mono-, di- or trisubstituted by phenyl or fluorine,
9) -CH(RH)-C(O)-NH2, 10) -CH(RI 1)-C(O)-NH-CH(R12)-CH2-OH,9) -CH (RH) -C (O) -NH 2 , 10) -CH (RI 1) -C (O) -NH-CH (R 12) -CH 2 -OH,
11) -(C-|-Cg)-Alkylen-Phenyl, wobei Phenyl oder Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Chlor, Fluor, -C(O)-O-RH , -(C<|-C4)-Alkyl-O-R11 , -O-(C-|-C4)-Alkyl, Phenyl oder11) - (C 1 -C 6) -alkylene-phenyl, where phenyl or alkylene is unsubstituted or independently of one another by chlorine, fluorine, -C (O) -O-RH, - (C < | -C 4) -Alkyl-O-R11, -O- (C-C4) -alkyl, phenyl or
-(C-|-C4)-Alkyl substituiert sind, 12) -CH(RI IKKOj-NH-tC-i^-Alkyl,- (C 1 -C 4) -alkyl, 12) -CH (R 1 IKKOj-NH-tC-i ^ -alkyl,
13) -(Co-C4)-Alkylen-C(R11 )(R12)-Bicyclo[3.1.1 ]heptanyl, wobei((Co-C 4) -alkylene-C (R11) R12) -bicyclo [3.1.1] heptanyl, wherein - 13)
Bicyclo[3.1.1]heptanyl unsubstituiert oder ein- bis vierfach durch -(Ci-C4)-Alkyl substituiert ist,Bicyclo [3.1.1] heptanyl is unsubstituted or substituted one to four times by - (C 1 -C 4) -alkyl,
14) -(C-|-C6)-Alkylen-C(O)-O-R11 , wobei Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Chlor, Fluor, -C(O)-O-RH , -(C<|-C4)-Alkyl-O-R11 , -O-(Ci-C4)-Alkyl, Phenyl oder -(Ci-C4)-Alkyl substituiert ist,14) - (C 1 -C 6) -alkylene-C (O) -O-R 11, where alkylene is unsubstituted or independently of one another by chlorine, fluorine, -C (O) -O-RH, - (C 1 -C 4) -alkyl-O-R 11, -O- (C 1 -C 4 ) -alkyl, phenyl or - (C 1 -C 4 ) -alkyl,
15) -(Co-C4)-Alkylen-C(R11)(R12)-C(O)-O-R11 , oder15) - (Co-C 4) -alkylene-C (R11) (R12) -C (O) -O-R11, or
16) -CH2-CF2-CF3, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom an das sie gebunden sind einen Mono- oder Bicyclischen Ring bilden, ausgewählt aus der Gruppe Pyrrolidine, 2-aza-bicyclo[3.2.2]nonan und 7-aza-bicyclo[2.2.1]heptan, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(C-|-C4)-Alkyl,16) -CH2-CF2-CF3, or the two radicals R6 together with the N-atom to which they are attached form a mono- or bicyclic ring selected from the group consisting of pyrrolidines, 2-aza-bicyclo [3.2.2 ] nonane and 7-aza-bicyclo [2.2.1] heptane, where the ring is unsubstituted or mono- or disubstituted by - (C 1 -C 4) -alkyl,
-C(O)-O-RH , -(C<|-C4)-Alkyl-O-R11 oder Phenyl substituiert ist, R7 für Wasserstoffatom oder -(C 1 -C4)-Alkyl steht,C (O) -O-RH, - (C 1-C4) -alkyl-O-R 11 or phenyl, R 7 is hydrogen or - (C 1 -C 4) -alkyl,
R9 für Wasserstoffatom oder -(C-|-C4)-Alkyl steht,R 9 is hydrogen or - (C 1 -C 4) -alkyl,
R11 und R12 gleich oder verschieden sind und unabhängig voneinander fürR11 and R12 are the same or different and independently of each other
1) Wasserstoff atom,1) hydrogen atom,
2) -(C1-C4J-AIkVl1 3) -(Crj-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch -OH, Halogen oder -O-(Ci-C4)-Alkyl substituiert ist,2) - (C 1 -C 4 -alkyl J 1 3) - (Cr j-C4) alkylene-phenyl, where phenyl is unsubstituted or independently mono-, di- or trisubstituted by OH, halogen or -O- ( Ci-C 4 ) -alkyl is substituted,
4) -(Crj-C4)-Alkylen-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adamantanyl, 1 ,7,7-Trimethyl-bicyclo[3.1.1 ]heptanyl, Octahydro-4,7-methano-indenyl oder4) - (Crj-C4) -alkylene- (C3-C12) -cycloalkyl, where cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, 1, 7,7-trimethyl-bicyclo [3.1.1] heptanyl, octahydro-4,7-methano-indenyl or
Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch -(Ci-C4)-Alkyl, -C(O)-O-R13 oder Phenyl substituiert ist, oderBicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or substituted independently of one another once, twice, three or four times by - (C 1 -C 4 ) -alkyl, -C (O) -O-R 13 or phenyl, or
5) -(Co-C4)-Alkylen-Indolyl, stehen, R13 für 1) Wasserstoffatom,5) - (Co-C4) -alkylene-indolyl, R13 is 1) hydrogen,
2) -(C^C^-Alkyl,2) - (C 1 -C 4) -alkyl,
3) -(C0-C4)-Alkylen-C(O)-O-R14,3) - (C 0 -C 4 ) -alkylene-C (O) -O-R 14,
4) -(C0-C4)-Alkylen-C(O)-R14 oder4) - (C 0 -C 4) -alkylene-C (O) -R 14 or
5) -(C0-C4)-Alkylen-O-R14 steht, R14 für Wasserstoffatom, -(C<|-C4)-Alkyl, -NH2 oder -OH steht und R15 für Wasserstoff atom, -(C<|-C4)-Alkyl, -O-CF3, -NH2, -OH, -CF3 oder Halogen steht.5) - (C 0 -C 4) -alkylene-O-R 14, R 14 is hydrogen, - (C 1 -C 4 ) -alkyl, -NH 2 or -OH and R 15 is hydrogen, - (C 1 -C 4 ) -alkyl, -O-CF 3, -NH 2, -OH, -CF3 or halogen.
10. Verwendung gemäß der Ansprüche 1 bis 9, dadurch gekennzeichnet, dass es sich um eine oder mehrere Erkrankungen aus der Reihe Myokardinfarkt, Angina pectoris und andere Formen des akuten Koronarsyndroms, den Schlaganfall, die peripher vaskulären Erkrankungen, die tiefe Venenthrombose, die Lungenembolie, embolische oder thrombotische Ereignisse bedingt durch kardiale Arrhythmien, kardiovaskuläre Ereignisse wie Restenose nach10. Use according to claims 1 to 9, characterized in that it is one or more diseases from the series myocardial infarction, angina pectoris and other forms of acute coronary syndrome, stroke, peripheral vascular diseases, deep vein thrombosis, pulmonary embolism, embolic or thrombotic events due to cardiac arrhythmias, cardiovascular events such as restenosis after
Revaskularisierung und Angioplastie und ähnlichen Eingriffen wie Stentimplantationen und Bypass-Operationen handelt, oder die Reduktion der Thrombosegefahr nach chirurgischen Eingriffen wie bei Knie- und Hüftgelenksoperationen, oder um die disseminierte intravaskuläre Koagulation, Sepsis und anderen intravaskulären Ereignissen, die mit einer Entzündung einhergehen, Atherosklerose, Diabetes und dem metabolischen Syndrom und deren Folgen, Tumorwachstum und Tumormetastasierung, entzündliche und degenerative Gelenkserkrankungen wie der rheumatoiden Arthritis und der Arthrose, Störungen des hämostatischen Systems wie Fibrinablagerungen, fibrotische Veränderungen der Lunge wie die chronische obstruktiveRevascularization and angioplasty and similar procedures such as stenting and bypass surgery, or the reduction of the risk of thrombosis following surgical procedures such as knee and hip joint surgery, or disseminated intravascular coagulation, sepsis, and other intravascular events associated with inflammation, atherosclerosis, Diabetes and the metabolic syndrome and its consequences, tumor growth and tumor metastasis, inflammatory and degenerative joint diseases such as rheumatoid arthritis and osteoarthritis, disorders of the hemostatic system such as fibrin deposits, fibrotic changes in the lungs as the chronic obstructive
Lungenerkrankung, das adult respiratory distress Syndrom oder Fibrinablagerungen des Auges nach Augenoperationen oder Verhinderung oder Behandlung von Narbenbildung handelt.Pulmonary disease, which is adult respiratory distress syndrome or fibrin deposition of the eye after eye surgery or prevention or treatment of scarring.
11. Verbindung der Formel11. Compound of the formula
Figure imgf000148_0001
und/oder einer stereoisomeren Form der Verbindung der Formel I und/oder Gemische dieser Formen in jedem Verhältnis, und/oder ein physiologisch verträgliches Salz der Verbindung der Formel I, wobei X für -SO2- steht,
Figure imgf000148_0001
and / or a stereoisomeric form of the compound of formula I and / or mixtures of these forms in any ratio, and / or a physiologically acceptable salt of the compound of formula I, wherein X is -SO 2 -,
R1 für 1) Wasserstoffatom,R1 for 1) hydrogen atom,
2) -(C1-Ce)-AIKyI,2) - (C 1 -Ce) -Alkyl,
3) -(Co-C4)-Alkylen-(C3-C-|2)-Cycloalkyl oder 4) -(C -|-C6)-Alkylen-(C6-C-J4)-Aryl steht,3) - (Co-C4) -alkylene- (C3-C- | 2) -cycloalkyl or 4) - (C - | -C6) -alkylene- (C6-C-J4) -aryl,
R2 für den Rest der Formel IlR2 for the rest of Formula II
-(A1)m-A2 (II) steht, worin m die ganze Zahl Null oder 1 bedeutet, A1 für 1) -(CH2)rr. worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet,- (A1) m -A2 (II), where m is the integer zero or 1, A1 is 1) - (CH2) rr. where n is the integer zero, 1, 2 or 3,
2) -NH-(CH2)n-. worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet,2) -NH- (CH 2) n -. where n is the integer zero, 1, 2 or 3,
3) -NH(Ci -C6)-Alkyl)-(CH2)n-, worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet,3) -NH (C 1 -C 6) -alkyl) - (CH 2) n -, where n is the integer zero, 1, 2 or 3,
4) -NH((C3-C6)-Cycloalkyl)-(CH2)n-, worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet,4) -NH ((C 3 -C 6) -cycloalkyl) - (CH 2) n -, where n is the integer zero, 1, 2 or 3,
5) -O-(CH2)rr> worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet, oder5) -O- (CH 2) rr > wherein n is the integer zero, 1, 2 or 3, or
6) -(CH2)rrSOx-, worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet und x die ganze Zahl Null, 1 oder 2 bedeutet, steht, A2 für 1) Het, wobei unter Het ein 4- bis 15-gliedriges heterocyclisches6) - (CH 2) r R SO x -, where n is the integer zero, 1, 2 or 3 and x is the integer zero, 1 or 2, A2 is 1) Het, where Het is a 4- to 15-membered heterocyclic
Ringsystem mit 4 bis 15 Ringatomen verstanden wird, die in ein, zwei oder drei miteinander verbundenen Ringsystemen vorliegen und die ein, zwei, drei oder vier gleiche oder verschiedene Heteroatome aus der Reihe Sauerstoff, Stickstoff oder Schwefel enthalten und unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch ein -(C-) -Ring system comprising 4 to 15 ring atoms which are present in one, two or three interconnected ring systems and which contain one, two, three or four identical or different heteroatoms from the series oxygen, nitrogen or sulfur and are unsubstituted or independently of one another, two or three times by a - (C-) -
C3)-Alkyl, Halogen, -NH2, -CF3 oder -O-CF3 substituiert ist,C3) -alkyl, halogen, -NH2, -CF3 or -O-CF3 is substituted,
2) -(C0-C6)-Alkylen-NH2 ,2) - (C 0 -C 6) -alkylene-NH 2,
3) -(C1-C6)-Alkylen-NH-C(=NH)-NH2, 4) -(C-|-C6)-Alkylen-NH-C(=NH)-(C<|-C4)-Alkyl, 5) -(Co-C4)-Alkylen-0-NH-C(=NH)-NH2,3) - (C 1 -C 6) -alkylene-NH-C (= NH) -NH 2, 4) - (C 1 -C 6) -alkylene-NH-C (= NH) - (C < | -C 4 ) alkyl, 5) - (Co-C4) -alkylene-O-NH-C (= NH) -NH 2,
6) -(Co-C4)-Alkylen-NH-C(O)-(C1-C6)-Alkyl,6) - (Co-C 4 ) -alkylene-NH-C (O) - (C 1 -C 6) -alkyl,
7) -(Ci-C6)-Alkylen-NH-C(O)-O-(Ci-C4)-Alkylen-Aryl, wobei Aryl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist,7) - (Ci-C6) -alkylene-NH-C (O) -O- (Ci-C4) -alkylene-aryl, wherein aryl is unsubstituted or substituted by -NH2 or by -NH2 and one, two or is substituted three times by R15,
8) -(C3-C8)-Cycloalkyl-NH2, oder8) - (C 3 -C 8) -cycloalkyl-NH 2 , or
9) -(Co-C4)-Alkylen-(C6-Ci4)-Aryl, wobei Aryl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist, steht, R3 für 1) -(C<|-C6)-Alkyl,9) - (Co-C4) alkylene- (C6-Ci4) aryl, wherein aryl is unsubstituted or substituted by -NH 2 or -NH 2, and mono-, di- or trisubstituted by R15,, R 3 represents 1) - (C 1 -C 6 ) -alkyl,
2) -(Co-C4)-Alkylen-(C3-Ci2)-Cycloalkyl,2) - (Co-C4) -alkylene- (C3-C12) -cycloalkyl,
3) -(C-|-C6)-Alkylen-(C6-C-i4)-Aryl, wobei Aryl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,3) - (C 1 -C 6) -alkylene- (C 6 -C 14) -aryl, where aryl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15,
4) -(C0-C8)-Alkylen-N(R5)-PG, 5) -(Ci-C6)-Alkylen-NH-C(O)-O-(Ci-C4)-Alkylen-Aryl, wobei Aryl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,4) - (C 0 -C 8 ) -alkylene-N (R 5) -PG, 5) - (C 1 -C 6 ) -alkylene-NH-C (O) -O- (C 1 -C 4 ) -alkylene-aryl in which aryl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15,
6) -(Co-C4)-Alkylen-(C6-Ci4)-Aryl-(Co-C4)-Alkylen-N(R5)-PG,6) - (Co-C4) -alkylene- (C6-C14) -aryl (Co-C4) -alkylene-N (R5) -PG,
7) -(C0-C8)-Alkylen-O-PG, 8) -(Co-C4)-Alkylen-(C6-Ci4)-Aryl-(Co-C4)-Alkylen-0-PG,7) - (C 0 -C 8 ) -alkylene-O-PG, 8) - (Co-C 4 ) -alkylene- (C 6 -C 14) -aryl (Co-C 4) -alkylene-0-PG,
9) -(C0-C8)-Alkylen-C(O)-O-PG,9) - (C 0 -C 8 ) -alkylene C (O) -O-PG,
10) -(Co-C4)-Alkylen-(C6-Ci4)-Aryl-(Co-C4)-Alkylen-C(0)-0-PG oder10) - (Co-C 4 ) -alkylene- (C 6 -C 14) -aryl (Co-C 4 ) -alkylene-C (O) -O-PG or
11) Wasserstoff atom, steht, R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander für11) hydrogen atom, R4 is -N (R6) 2, where R6 are the same or different and independently of one another
1) Wasserstoffatom,1) hydrogen atom,
2) -(C-i-C^-Alkyl,2) - (C 1 -C 4) -alkyl,
3) -(Co-C4)-Alkylen-(C3-Ci2)-Cyc'oalkyl. wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R11 , Halogen, -C(O)-O-RH , -(Ci-C4)-Alkyl-O-R11 oder -O-(C<|-C4)-Alkyl substituiert ist,3) - (Co-C4) -alkylene- (C3-Ci2) - C y c 'OAlk yl. where cycloalkyl is unsubstituted or independently of one another once, twice, three or four times by R 11, Halogen, -C (O) -O-RH, - (C 1 -C 4 ) -alkyl-O-R 11 or -O- (C 1 -C 4) -alkyl,
4) -(Co-C6)-Aikylen-(C6-Ci4)-Aryl, wobei Aryl und Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R11 , Halogen, -C(O)-O-R11 , -(C-|-C4)-Alkyl-O-R11 , -C(O)-N(R8)2 oder4) - (Co-C6) -alkylene- (C6-C14) -aryl, where aryl and alkylene are unsubstituted or independently of one another once, twice, three or four times by R11, halogen, -C (O) -O- R 11, - (C 1 -C 4 ) -alkyl-O-R 11, -C (O) -N (R 8) 2 or
-O-(Ci-C4)-Alkyl substituiert sind,-O- (C 1 -C 4) -alkyl are substituted,
5) -(C0-C8)-Alkylen-N(R5)-PG,5) - (C 0 -C 8 ) -alkylene-N (R 5) -PG,
6) -(CO-C4)-Alkylen-(C6-Ci4)-Aryl-(Co-C4)-Alkyl-N(R5)-PG,6) - (C 0 -C 4 ) -alkylene- (C 6 -C 14) -aryl (Co-C 4 ) -alkyl-N (R 5) -PG,
7) -(C0-C8)-Alkylen-O-PG, 8) -(Co-C4)-Alkylen-(C6-C14)-Aryl-(Co-C4)-Alkyl-O-PG,7) - (C 0 -C 8 ) -alkylene-O-PG, 8) - (Co-C 4 ) -alkylene- (C 6 -C 14 ) -aryl (Co-C 4 ) -alkyl-O-PG .
9) -(C0-C8)-Alkylen-C(O)-O-R11 ,9) - (C 0 -C 8 ) -alkylene-C (O) -O-R 11,
10) -(Co-C4)-Alky!en-(C6-Ci4)-Aryl-(Co-C4)-Alkyl-C(O)-O-PG,10) - (C 1 -C 4) -alkyl- (C 6 -C 14) -aryl (C 1 -C 4) -alkyl-C (O) -O-PG,
11 ) -(Co-C4)-Alkylen-Het, wobei unter Het ein 4- bis 15-gliedriges heterocyclisches Ringsystem verstanden wird mit 4 bis 15 Ringatomen, die in ein, zwei oder drei miteinander verbundenen Ringsystemen vorliegen und die ein, zwei, drei oder vier gleiche oder verschiedene Heteroatome aus der Reihe Sauerstoff, Stickstoff oder Schwefel enthalten, wobei Het oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-RH , -(Ci-C4)-Alkyl-O-R11 oder -O-(C<|-C4)-Alkyl substituiert sind,11) - (Co-C4) -alkylene-Het, where Het is a 4- to 15-membered heterocyclic ring system is understood with 4 to 15 ring atoms, which are present in one, two or three interconnected ring systems and the one, two, contain three or four identical or different heteroatoms from the series oxygen, nitrogen or sulfur, wherein Het or alkylene is unsubstituted or independently of one another once, twice or three times by R11, halogen, -C (O) -O-RH, - (Ci -C 4 ) -alkyl-O-R 11 or -O- (C 1 -C 4 ) -alkyl,
12) -(C<|-C3)-Fluoralkyl,12) - (C 1 -C 3) fluoroalkyl,
13) -(C0-C4)-Alkylen-CH(R11 )-C(O)-NH2,13) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH 2,
14) -(Co-C4)-Alky!en-CH(R11)-C(O)-NH-(Ci-C4)-Alkyl,14) - (Co-C 4 ) -alkyl-CH (R 11) -C (O) -NH- (C 1 -C 4 ) -alkyl,
15) -(C0-C4)-Alkylen-CH(R11 )-C(O)-NH-CH(R12)-R13, oder 16) Aminosäure, wobei die Bindung der Aminosäure über eine Peptid-15) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH-CH (R 12) -R 13, or 16) amino acid, wherein the binding of the amino acid via a peptide
Bindung erfolgt und der Carboxyl-Rest der Aminosäure unsubstituiert oder durch PG oder durch -N(R5)2 substituiert ist, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom, an das sie gebunden sind, einen mono- oder bicyciischen Ring mit 4 bis 9 Ringatomen bilden, der gesättigt, teilweise gesättigt oder aromatisch ist, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(C-|-C4)-Alkyl, -C(O)-O-R11 , Halogen, -(C-|-C4)-Alkyl-O-R11 oder Phenyl substituiert ist, R5 für Wasserstoffatom oder-(C-|-C6)-Alkyl steht,Binding takes place and the carboxyl radical of the amino acid is unsubstituted or substituted by PG or by -N (R5) 2, or the two radicals R6 together with the N-atom to which they are attached, a mono- or bicyciischen ring with 4 to 9 ring atoms, which is saturated, partially saturated or aromatic, the ring being unsubstituted or monosubstituted or disubstituted by - (C 1 -C 4) alkyl, C (O) -O-R 11, halogen, - (C 1 -C 4) alkyl-O-R 11 or phenyl, R 5 is Is hydrogen or (C 1 -C 6) -alkyl,
PG füreine Schutzgruppe für die Amino-, Carboxyl- oder für die Hydroxyfunktion steht,PG is a protective group for the amino, carboxyl or hydroxyl function,
R7 für Wasserstoffatom oder -(C<|-C6)-Alkyl steht,R 7 is hydrogen or - (C 1 -C 6) -alkyl,
R8 für Wasserstoffatom oder -(C-|-C6)-Alkyl steht, R9 für Wasserstoffatom oder -(C-|-C6)-Alkyl steht,R 8 is hydrogen or - (C 1 -C 6) -alkyl, R 9 is hydrogen or - (C 1 -C 6) -alkyl,
R11 und R12 gleich oder verschieden sind und unabhängig voneinander für 1) Wasserstoff atom,R 11 and R 12 are identical or different and independently of one another represent 1) hydrogen atom,
2) -(C1-Ce)-AIlCyI1 2) - (C 1 -Ce) -Alalyxy 1
3) -(Co-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder oder unabhängig voneinander ein-, zwei- oder dreifach durch Halogen, -OH oder -O-(C-|-C4)-Alkyl substituiert ist, 4) -(Crj-C4)-Alkylen-(C3-C-|2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R13, Halogen, -C(O)-O-RI 3, -(Ci-C4)-Alkyl-O-R13, -O-(Ci-C4)-Alkyl oder3) - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or independently or monosubstituted, disubstituted or trisubstituted by halogen, -OH or -O- (C 1 -C 4) -alkyl, 4) - (Crj-C4) -alkylene- (C3-C- | 2) -cycloalkyl, wherein cycloalkyl unsubstituted or independently of one another once, twice, three or four times by R13, halogen, -C (O) -O-RI 3, - (Ci-C 4 ) -alkyl-O-R13, -O- (Ci-C 4 ) alkyl or
-(Crj-C4)-Alkylen-Phenyl substituiert ist, 5) -(C0-C4)-Alkylen-C(O)-N(R13)2 oder 6) -(Crj-C4)-Alky!en-Indolyl, stehen,(C 1 -C 4 ) -alkylene-phenyl, 5) - (C 0 -C 4 ) -alkylene-C (O) -N (R 13) 2 or 6) - (C 1 -C 4 ) -alky- Indolyl, stand,
R13 für 1 ) Wasserstoff atom,R13 for 1) hydrogen atom,
2) -(C1-C4)-Alkyl,2) - (C 1 -C 4 ) -alkyl,
3) -(C0-C4)-Alkylen-C(O)-O-R14,3) - (C 0 -C 4 ) -alkylene-C (O) -O-R 14,
4) -(C0-C4)-Alkylen-C(O)-R14 oder 5) -(C0-C4)-Alkylen-O-R14 steht,4) - (C 0 -C 4 ) -alkylene-C (O) -R 14 or 5) - (C 0 -C 4) -alkylene-O-R 14,
R14 für Wasserstoffatom, -(C<|-C4)-Alkyl, -NH2 oder -OH, steht und R15 für Wasserstoff atom, -(C-|-C4)-Alkyl, -O-CF3, -NH2, -OH, -CF3 oder Halogen steht. R 14 is hydrogen, - (C 1 -C 4) -alkyl, -NH 2 or -OH, and R 15 is hydrogen, - (C 1 -C 4) -alkyl, -O-CF 3, -NH 2, -OH, -CF3 or halogen.
12. Verbindung der Formel I gemäß Anspruch 11 , wobei R1 für 1) Wasserstoffatom oder12. A compound of formula I according to claim 11, wherein R 1 is hydrogen or
2) -(C<|-C4)-Alkyl, steht, R2 für 1) -(C1-C6)-Alkylen-NH2, 2) -(Co-C4)-Alkylen-Pyridyl-NH2,2) - (C <| -C4) alkyl, R 2 is 1) - (C 1 -C 6) alkylene-NH 2, 2) - (Co-C4) -alkylene-pyridyl-NH 2,
3) -(C0-C4)-Alkylen-Piperidinyl-NH2,3) - (C 0 -C 4) -alkylene-piperidinyl-NH 2,
4) -(Co-C4)-Alkylen-Thiazolyl-NH2,4) - (Co-C 4 ) -alkylene-thiazolyl-NH 2 ,
5) -(C1-C6)-Alkylen-NH-C(=NH)-NH2,5) - (C 1 -C 6) -alkylene-NH-C (= NH) -NH 2 ,
6) -(Co-C4)-Alkylen-(C3-C8)-Cycloalkyl-NH2, 7) -(C1-C6)-Alkylen-NH-C(=NH)-(Ci-C4)-AlkylI 6) - (Co-C 4 ) -alkylene- (C 3 -C 8) -cycloalkyl-NH 2 , 7) - (C 1 -C 6 ) -alkylene-NH-C (= NH) - (C 1 -C 4 ) -Alkyl I
8) -(C0-C4)-Alkylen-O-NH-C(=NH)-NH2i 8) - (C 0 -C 4 ) -alkylene-O-NH-C (= NH) -NH 2i
9) -(C1-C6)-Alkylen-NH-C(O)-O-(Ci-C4)-Alkylen-Aryl, wobei Aryl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist, 10) -(Co-C4)-Alkylen-NH-C(0)-(Ci-C4)-Alkyl,9) - (C 1 -C 6) -alkylene-NH-C (O) -O- (Ci-C 4) -alkylene-aryl, wherein aryl is unsubstituted or substituted by -NH 2 or -NH 2, and mono- which is substituted twice or three times by R 15, 10) - (Co-C 4) -alkylene-NH-C (O) - (C 1 -C 4) -alkyl,
11) -(Co-C4)-Alkylen-(C6-C-|4)-Aryl, wobei Aryl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist, oder11) - (Co-C4) alkylene- (C6-C- | 4) -aryl, wherein aryl is unsubstituted or substituted by -NH 2 or -NH 2, and mono-, di- or trisubstituted by R15 , or
12) -(C-i-C4)-Alkylen-SOχ-(C-|-C4)-Alkylen-NH2 worin x die ganze Zahl Null, 1 oder 2 bedeutet, steht,12) - (C 1 -C 4 ) -alkylene-SOχ- (C 1 -C 4 ) -alkylene-NH 2 in which x is the integer zero, 1 or 2,
R3 für 1) -(C"|-C4)-Alkyl,R 3 is 1) - (C 1 -C 4 ) -alkyl,
2) -(C0-C4)-Alkylen-(C3-C8)-Cycloalkyl,2) - (C 0 -C 4 ) -alkylene- (C 3 -C 8 ) -cycloalkyl,
3) -(C-|-C6)-Alkylen-Aryl, wobei Aryl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist, 4) -(C i-Ce)-Alkylen-N H-C(O)-O-(C 1-C4)-Alkylen-Aryl, wobei Aryl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,3) - (C 1 -C 6) -alkylene-aryl, wherein aryl is independently substituted once, twice or three times by R 15, 4) - (C 1 -C 6) -alkylene-N HC (O) -O - (C 1 -C 4 ) -alkylene-aryl, where aryl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15,
5) -(C-|-C6)-Alkylen-NH-PG,5) - (C 1 -C 6) -alkylene-NH-PG,
6) -(C-|-C6)-Alkylen-O-PG, 7) -(C1-Ce)-AIkYl, oder6) - (C 1 -C 6) -alkylene-O-PG, 7) - (C 1 -Ce) -AlkYl, or
8) Wasserstoffatom, steht, wobei PG für t-Butyl-, t-Butyloxycarbonyl oder Benzyloxycarbonyl steht, R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander für8) hydrogen, wherein PG is t-butyl, t-butyloxycarbonyl or benzyloxycarbonyl, R4 is -N (R6) 2, wherein R6 are the same or different and independently of one another
1) Wasserstoffatom,1) hydrogen atom,
2) -(C1-Ce)-AIkYl,2) - (C 1 -Ce) -Alkyl,
3) -(Co-C4)-Alkylen-(C3-C12)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R11 , Halogen, -C(O)-O-RH , -(C-j-C^-Alkyl-O-RH oder3) - (C 1 -C 4) -alkylene- (C 3 -C 12) -cycloalkyl, where cycloalkyl is unsubstituted or independently of one another once, twice, three or four times by R 11, halogen, -C (O) -O- RH, - (CjC ^ alkyl-O-RH or
-O-(C1-C4)-Alkyl substituiert ist,-O- (C 1 -C 4) -alkyl is substituted,
4) -(Co-C4)-Alkylen-C(R11)(R12HC3-C-|2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-RH , -(C-i-C^-Alkyl-O-RH oder -O-(C1-C4)-Alkyl substituiert ist,4) - (Co-C4) -alkylene-C (R11) (R12HC3-C- | 2) -cycloalkyl, where cycloalkyl is unsubstituted or independently mono-, di- or trisubstituted by R11, halogen, -C (O) - O-RH, - (C 1 -C 4 -alkyl-O-RH or -O- (C 1 -C 4) -alkyl,
5) -(Crj-C4)-Alkylen-Het, wobei unter Het ein 4- bis 15-gliedriges heterocyclisches Ringsystem verstanden wird mit 4 bis 15 Ringatomen, die in ein, zwei oder drei miteinander verbundenen Ringsystemen vorliegen und die ein, zwei, drei oder vier gleiche oder verschiedene Heteroatome aus der Reihe Sauerstoff, Stickstoff oder Schwefel enthalten, wobei Het oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-RH , -(C1-C^)-AIkYl-O-RH oder -0-(C1 -C4)-Alkyl substituiert sind, 6) -(Crj-C6)-Alkylen-Aryl, wobei Aryl oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-RH , -(C0-C4)-Alkyl-O-R11 oder -0-(C1 -C4)-Alkyl substituiert sind, 7) -(C0-C4)-Alkylen-C(R11)(R12)-Aryl, wobei Aryl oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-RH , -(Co-C4)-Alkyl-O-R11 oder -O-(C-|-C4)-Alkyl substituiert sind,5) - (Crj-C4) -alkylene-Het, wherein Het is a 4- to 15-membered heterocyclic ring system is understood with 4 to 15 ring atoms, which are present in one, two or three interconnected ring systems and the one, two, contain three or four identical or different heteroatoms from the series oxygen, nitrogen or sulfur, wherein Het or alkylene is unsubstituted or independently of one another once, twice or three times by R11, halogen, -C (O) -O-RH, - (C C 1 -C 4) -Alkyl-O-RH or -O- (C 1 -C 4) -alkyl, 6) - (C 1 -C 6) -alkylene-aryl, where aryl or alkylene is unsubstituted or independently of one another, are substituted twice or three times by R 11, halogen, -C (O) -O-RH, - (C 0 -C 4) -alkyl-O-R 11 or -O- (C 1 -C 4) -alkyl, 7) - (C 0 -C 4) -alkylene-C (R 11) (R 12) -aryl, where aryl or alkylene are unsubstituted or independently of one another, mono-, di- or trisubstituted substituted alkyl, | (Co-C 4) -alkyl-O-R11 or -O- (C4 C-) - by R11, halogen, -C (O) -O-RH,
8) 1 ,2,3,4-Tetrahydro-naphthalenyl,8) 1, 2,3,4-tetrahydro-naphthalenyl,
9) -(Crj-C4)-Alkylen-CH(R11 )-C(O)-NH2, 10) -(Co-C4)-Alkylen-CH(R11)-C(O)-NH-(C-|-C4)-Alkyl,9) - (Crj-C4) -alkylene-CH (R11) -C (O) -NH2, 10) - (Co-C4) -alkylene-CH (R11) -C (O) -NH- (C- | -C 4 ) -alkyl,
11 ) -(Crj-C4)-Alkylen-CH(R11 )-C(O)-NH-CH(R12)-R13,11) - (Crj-C4) -alkylene-CH (R11) -C (O) -NH-CH (R12) -R13,
12) -(Crj-C6)-Alkylen-C(O)-O-R11 , wobei Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch R11 , Halogen, -C(O)-O-R11 , -(C-|-C4)-Alkyl-O-R11 oder -O-(C-|-C4)-Alkyl substituiert ist, 13) -(Co-C4)-Alkylen-C(R11)(R12)-C(O)-O-R11 , oder12) - (Crj-C6) -alkylene-C (O) -O-R11, wherein alkyls are unsubstituted or independently of one another once or twice by R11, halogen, -C (O) -O-R11, - (C- | -C 4) -alkyl-O-R 11 or -O- (C 1 -C 4) -alkyl, 13) - (C 1 -C 4 ) -alkylene-C (R 11) (R 12) -C (O) - O-R11, or
14) -(C-j-C3)-Fluoralkyl, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom, an das sie gebunden sind, einen mono- oder bicyclischen Ring mit 4 bis 9 Ringatomen bilden, der gesättigt, teilweise gesättigt oder aromatisch ist, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(C<| -C4)-Alkyl, -C(O)-O-R11 ,14) - (Cj-C3) -Fluoralkyl, or the two radicals R6 together with the N-atom to which they are attached form a mono- or bicyclic ring having 4 to 9 ring atoms, the saturated, partially saturated or is aromatic, which ring is unsubstituted or mono- or disubstituted by - (C 1 -C 4) -alkyl, -C (O) -O-R 11,
Halogen, -(C-i-C4)-Alkyl-O-R11 oder Phenyl substituiert ist, R7 für Wasserstoffatom oder -(C-|-C4)-Alkyl steht, R9 für Wasserstoffatom oder -(C-|-C4)-Alkyl steht,Halogen, - (Ci-C4) -alkyl-O-R11 or phenyl, R7 is hydrogen or - (C- | -C4) alkyl, R9 is hydrogen or - (C- | -C4) alkyl .
R11 und R12 gleich oder verschieden sind und unabhängig voneinander für 1) Wasserstoff atom,R 11 and R 12 are identical or different and independently of one another represent 1) hydrogen atom,
2) -(C-i-C^-Alkyl,2) - (C 1 -C 4) -alkyl,
3) -(Crj-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch Halogen, -OH oder -O-(C-|-C4)-Alkyl substituiert ist, 4) -(Crj-C4)-Alkylen-(C3-Ci2)-Cyc|oalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R13, Halogen, -C(O)-O-R13, -(C-|-C4)-Alkyl-O-R13, -O-(Ci-C4)-Alkyl oder3) - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or independently of one another mono-, di- or trisubstituted by halogen, -OH or -O- (C 1 -C 4) -alkyl, 4) (Crj-C4) -alkylene- (C3-Ci2) - C y c | oalkyl, wherein cycloalkyl is unsubstituted or independently of one another once, twice, three or four times by R13, halogen, -C (O) -O-R13, - (C-C4) -alkyl-O-R13, -O - (Ci-C 4 ) -alkyl or
-(Crj-C4)-Alkylen-Phenyl substituiert ist,- (Crj-C4) -alkylene-phenyl is substituted,
5) -(C0-C4)-Alkylen-C(O)-N(R13)2 oder 6) -(Co-C4)-Alkylen-Indolyl, stehen,5) - (C 0 -C 4 ) -alkylene-C (O) -N (R 13) 2 or 6) - (Co-C4) -alkylene-indolyl,
R13 für 1 ) Wasserstoffatom,R 13 is 1) hydrogen,
2) -(C-|-C4)-Alkyl,2) - (C 1 -C 4 ) -alkyl,
3) -(C0-C4)-Alkylen-C(O)-O-R14, 4) -(C0-C4)-Alkylen-C(O)-R14 oder3) - (C 0 -C 4 ) -alkylene-C (O) -O-R 14, 4) - (C 0 -C 4 ) -alkylene-C (O) -R 14 or
5) -(C0-C4)-Alkylen-O-R14 steht,5) - (C 0 -C 4 ) -alkylene-O-R 14,
R14 für Wasserstoff atom, -(C-|-C4)-Alkyl, -NH2 oder -OH, steht und R15 für Wasserstoffatom, -(C-i-C^-Alkyl, -O-CF3, -NH2, -OH, -CF3 oderR 14 is hydrogen atom, - (C 1 -C 4 ) -alkyl, -NH 2 or -OH, and R 15 is hydrogen, - (C 1 -C 4 -alkyl, -O-CF 3, -NH 2 , -OH, -CF 3 or
Halogen steht.Halogen is available.
13. Verbindung der Formel I gemäß Anspruch 11 oder 12, wobei R1 für 1) Wasserstoffatom oder13. A compound of formula I according to claim 11 or 12, wherein R 1 is hydrogen or
2) -(Ci-C4)-Alkyl, steht,2) - (C 1 -C 4 ) -alkyl,
R2 für 1) -(C-|-C6)-Alkylen-NH2, 2) -(C<|-C4)-Alkylen-Pyridyl-NH2,R2 is 1) - (C- | -C6) alkylene-NH 2, 2) - (C <| -C4) alkylene-pyridyl-NH 2,
3) -(C-|-C4)-Alkylen-Piperidinyl-NH2,3) - (C 1 -C 4 ) -alkylene-piperidinyl-NH 2,
4) -(C1-C6)-Alkylen-NH-C(=NH)-NH2,4) - (C 1 -C 6) -alkylene-NH-C (= NH) -NH 2 ,
5) -(C0-C4)-Alkylen-(C3-C6)-Cycloalkyl-NH2,5) - (C 0 -C 4 ) -alkylene- (C 3 -C 6 ) -cycloalkyl-NH 2 ,
6) -(C-i-C6)-Alkylen-NH-C(=NH)-(Ci-C4)-Alkyl, 7) -(Ci-C4)-Alkylen-O-NH-C(=NH)-NH2) 6) - (C 1 -C 6) -alkylene-NH-C (NHNH) - (C 1 -C 4 ) -alkyl, 7) - (C 1 -C 4 ) -alkylene-O-NH-C (NHNH) - NH2 )
8) -(Ci-C6)-Alkylen-NH-C(O)-O-(Ci-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist,8) - (Ci-C6) alkylene-NH-C (O) -O- (Ci-C 4) -alkylene-phenyl, wherein phenyl is unsubstituted or substituted by -NH 2 or -NH 2, and mono-, is substituted two or three times by R 15,
9) -(C1-C4)-Alkylen-NH-C(O)-(C1-C6)-Alkyl, 10) -(C-|-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch -9) - (C 1 -C 4 ) -alkylene-NH-C (O) - (C 1 -C 6) -alkyl, 10) - (C-C 4 ) -alkylene-phenyl, wherein phenyl is unsubstituted or substituted by -
NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist,NH 2 is substituted by -NH 2 and mono-, di- or trisubstituted by R 15,
11) -(Ci-C4)-Alkylen-SO2-(Ci-C4)-Alkylen-NH2, oder11) - (Ci-C 4) -alkylene-SO2- (Ci-C 4) -alkylene-NH2, or
12) -(Ci-C4)-Alkylen-S-(C1-C4)-Alkylen-NH2, steht, 18912) - (Ci-C 4) -alkylene-S- (C 1 -C 4) alkylene-NH 2, is, 189
Harnstoff- und Sulfamidderivate als Inhibitoren von TAFIaUrea and sulfamide derivatives as inhibitors of TAFIa
Die Erfindung betrifft Verbindungen der Formel IThe invention relates to compounds of the formula I.
die Inhibitoren von aktivierter Thrombin-aktivierbarer Fibrinolyse Inhibitor sind. Die Verbindungen der Formel I eignen sich zur Herstellung von Arzneimitteln zur Prophylaxe, Sekundärprevention und Therapie von einer oder mehrerer Erkrankungen, die mit Thrombosen, Embolien, Hyperkoagulabilität oder fibrotischen Veränderungen einhergehen. which are inhibitors of activated thrombin-activatable fibrinolysis inhibitor. The compounds of the formula I are suitable for the preparation of medicaments for the prophylaxis, secondary prevention and therapy of one or more diseases which are accompanied by thromboses, embolisms, hypercoagulability or fibrotic changes.
156156
R3 für 1) -(C1-C4)-Alkyl,R 3 is 1) - (C 1 -C 4 ) -alkyl,
2) -(C1 -C4)-Alkylen-(C3-C6)-Cycloalkyl,2) - (C 1 -C 4 ) -alkylene- (C 3 -C 6 ) -cycloalkyl,
3) -(C-|-C4)-Alkylen-Phenyl, wobei Phenyl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist, 4) -(C-i-C6)-Alkylen-NH-C(O)-O-(Ci-C4)-Alkylen-Phenyl, wobei3) - (C 1 -C 4) -alkylene-phenyl, where phenyl is substituted independently of one another once, twice or three times by R 15, 4) - (C 1 -C 6) -alkylene-NH-C (O) -O - (Ci-C4) -alkylene-phenyl, wherein
Phenyl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,Phenyl is independently substituted once, twice or three times by R 15,
5) Wasserstoffatom steht, R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander für5) is hydrogen, R4 is -N (R6) 2, where R6 are the same or different and independently of one another
1) Wasserstoffatom,1) hydrogen atom,
2) -(C-i-C^-Alkyl,2) - (C 1 -C 4) -alkyl,
3) -(CQ-C4)-Alkylen-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adamantanyl, 1 ,7,7-Trimethyl-bicyclo[3.1.1 ]heptanyl, Decahydro-naphthalenyl,3) - (CQ-C4) -alkylene- (C3-C12) -cycloalkyl, where cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, 1, 7,7-trimethyl-bicyclo [3.1.1] heptanyl, decahydro-naphthalenyl,
Tetrahydronaphthalenyl, Octahydro-4,7-methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach substituiert ist durch -(C-|-C4)-Alkyl, -C(O)-O-RH oder -(C-|-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch Halogen substituiert ist,Tetrahydronaphthalenyl, octahydro-4,7-methanoindenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently of one another mono-, di-, tri- or tetra-substituted by - (C 1 -C 4) -alkyl, -C (O) -O-RH or - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or substituted by halogen,
4) -(Co-C4)-Alkylen-C(R11)(R12)-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adamantanyl, 1 ,7,7-Trimethyl-bicyclo[3.1.1]heptanyl, Decahydro- naphthalen, Tetrahydronaphthalenyl, Octahydro-4,7-methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach substituiert ist durch -(C-|-C4)-Alkyl, -C(O)-O-RH oder -(C<|-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch Halogen substituiert ist,4) - (Co-C4) -alkylene-C (R11) (R12) - (C3-C12) -cycloalkyl, where cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, 1, 7,7- Trimethyl-bicyclo [3.1.1] heptanyl, decahydronaphthalene, tetrahydronaphthalenyl, octahydro-4,7-methanoindenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently of one another, mono-, di-, tri- or tetravalent is substituted by - (C 1 -C 4) -alkyl, -C (O) -O-RH or - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or substituted by halogen,
5) -(Co-C4)-Alkylen-Het, wobei Het ausgewählt ist aus der Gruppe Acridinyl, Azepinyl, Azetidinyl, Aziridinyl, Benzimidazalinyl, Benzimidazolyl,5) - (Co-C4) -alkylene-Het, wherein Het is selected from the group acridinyl, azepinyl, azetidinyl, aziridinyl, benzimidazalinyl, benzimidazolyl,
Benzo[1 ,3]dioxolyl, Benzofuranyl, Benzothiofuranyl, Benzothiophenyl, 157Benzo [1,3] dioxolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, 157
Benzoxazolyl, Benzthiazolyl, Benztriazolyl, Benztetrazolyl, Benzisoxazolyl, Benzisothiazolyl, Carbazolyl, 4aH-Carbazolyl, Carbolinyl, Chinazolinyl, Chinolinyl, 4H-Chinolizinyl, Chinoxalinyl, Chinuclidinyl, Chromanyl, Chromenyl, Cinnolinyl, Deca-hydrochinolinyl, Dibenzofuranyl, Dibenzothiophenyl, Dihydrofuran[2,3-b]-tetrahydrofuranyl, Dihydrofuranyl, Dioxolyl, Dioxanyl, 2H,Benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dibenzofuranyl, dibenzothiophenyl, dihydrofuran [2, 3-b] -tetrahydrofuranyl, dihydrofuranyl, dioxolyl, dioxanyl, 2H,
6H-1 ,5,2-Dithiazinyl, Furanyl, Furazanyl, Imidazolidinyl, Imidazolinyl, Imidazolyl, 1 H-lndazolyl, Indolinyl, Indolizinyl, Indolyl, 3H-lndolyl, Isobenzofuranyl, Isochromanyl, Isoindazolyl, Isoindolinyl, Isoindolyl, Isochinolinyl (Benzimidazolyl), Isothiazolidinyl, 2-lsothiazolinyl, Isothiazolyl, Isoxazolyl, Isoxazolidinyl, 2-lsoxazolinyl, Morpholinyl, Naphthyridinyl,6H-1, 5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazinyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), Isothiazolidinyl, 2-isothiazolinyl, isothiazolyl, isoxazolyl, isoxazolidinyl, 2-isoxazolinyl, morpholinyl, naphthyridinyl,
Octahydroisochinolinyl, Oxadiazolyl, 1 ,2,3-Oxadiazolyl, 1 ,2,4-Oxadiazolyl, 1 ,2,5- Oxadiazolyl, 1 ,3,4-Oxadiazolyl, Oxazolidinyl, Oxazolyl, Oxazolidinyl, Oxothiolanyl, Pyrimidinyl, Phenanthridinyl, Phenanthrolinyl, Phenazinyl, Phenothiazinyl, Phenoxathiinyl, Phenoxazinyl, Phthalazinyl, Piperazinyl, Piperidinyl, Pteridinyl, Purynyl, Pyranyl, Pyrazinyl, Pyroazolidinyl, Pyrazolinyl,Octahydroisoquinolinyl, oxadiazolyl, 1, 2,3-oxadiazolyl, 1, 2,4-oxadiazolyl, 1, 2,5-oxadiazolyl, 1, 3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, oxothiolanyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, Phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl,
Pyrazolyl, Pyridazinyl, Pryidooxazolyl, Pyridoimidazolyl, Pyridothiazolyl, Pyridothiophenyl, Pyridinyl, Pyridyl, Pyrimidinyl, Pyrrolidinyl, Pyrrolinyl, 2H- Pyrrolyl, Pyrrolyl, Tetrahydrofuranyl, Tetrahydroisochinolinyl, Tetrahydrochinolinyl, Tetrahydropyridinyl, 6H-1 ,2,5-Thiadazinyl, 1 ,2,3- Thiadiazolyl, 1 ,2,4-Thiadiazolyl, 1 ,2,5-Thiadiazolyl, 1 ,3,4-Thiadiazolyl,Pyrazolyl, pyridazinyl, pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl, 6H-1,2,5-thiadazinyl, 1, 2 3-thiadiazolyl, 1, 2,4-thiadiazolyl, 1, 2,5-thiadiazolyl, 1, 3,4-thiadiazolyl,
Thianthrenyl, Thiazolyl, Thienyl, Thienoimidazolyl, Thienooxazolyl, Thienopyridin, Thienothiazolyl, Thiomorpholinyl, Thiophenyl, Triazinyl, 1 ,2,3- Triazolyl, 1 ,2,3-Triazolyl, 1 ,2,4-Triazolyl, 1 ,2,5-Triazolyl, 1,3,4-Triazolyl und Xanthenyl, wobei Het oder Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch -(C-|-C4)-Alkyl substituiert istThianthrenyl, thiazolyl, thienyl, thienoimidazolyl, thienooxazolyl, thienopyridine, thienothiazolyl, thiomorpholinyl, thiophenyl, triazinyl, 1, 2,3-triazolyl, 1, 2,3-triazolyl, 1, 2,4-triazolyl, 1, 2,5- Triazolyl, 1,3,4-triazolyl and xanthenyl, wherein Het or alkylene is unsubstituted or independently of one another mono- or disubstituted by - (C 1 -C 4) -alkyl
6) -(C-|-C6)-Alkylen-Phenyl, wobei Phenyl oder Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Halogen, Phenyl, -C(O)-O-RH , -(C<|-C4)-Alkyl-O-R11 , -O-(C-|-C4)-Alkyl oder -(C-i-C4)-Alkyl substituiert sind, 7) -(Crj-C4)-Alkylen-C(R11 )(R12)-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch Phenyl oder Fluor substituiert ist, 1586) - (C 1 -C 6) -alkylene-phenyl, where phenyl or alkylene is unsubstituted or independently of one another by halogen, phenyl, -C (O) -O-RH, - (C <| -C 4) Alkyl-O-R11, -O- (C 1 -C 4) -alkyl or - (C 1 -C 4) -alkyl, 7) - (C 1 -C 4) -alkylene-C (R 11) (R 12) - Phenyl, where phenyl is unsubstituted or independently of one another monosubstituted, disubstituted or trisubstituted by phenyl or fluorine, 158
8) 1 ,2,3,4-Tetrahydro-naphthalenyl,8) 1, 2,3,4-tetrahydro-naphthalenyl,
9) -(Co-C4)-Alkylen-CH(R11 )-C(O)-NH2,9) - (Co-C 4 ) -alkylene-CH (R 11) -C (O) -NH 2 ,
10) -(Co-C4)-Alkylen-CH(R11)-C(O)-NH-(C1 -C4)-Alkyl,10) - (Co-C4) alkylene-CH (R11) -C (O) -NH- (C 1 -C 4) -alkyl,
11 ) -(Co-C4)-Alkylen-CH(R11 )-C(O)-NH-CH(R12)-R13, 12) -(C-|-C6)-Alkylen-C(O)-O-R11 , wobei Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Halogen, Phenyl, -C(O)-O-RH , -(C-i -C4)-Alkyl-O-R11 , -O-(C-|-C4)-Alkyl oder -(C-j-C4)-Alkyl substituiert ist,11) - (C 1 -C 4) -alkylene-CH (R 11) -C (O) -NH-CH (R 12) -R 13, 12) - (C 1 -C 6) -alkylene C (O) -O- R 11, where alkylene is unsubstituted or independently of one another once or twice by halogen, phenyl, -C (O) -O-RH, - (C 1 -C 4) -alkyl-O-R 11, -O- (C 1 -C 4) Alkyl or - (Cj-C4) -alkyl,
13) -(C0-C4)-Alkylen-C(R11 )(R12)-C(O)-O-R11 , oder 14) -(C-I -C3)-Fluoralkyl, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom an das sie gebunden sind einen Mono- oder Bicyclischen Ring bilden ausgewählt aus der Gruppe Pyrrolidin, Piperidin, 2-Aza-bicyclo[3.2.2]nonan und 7-Aza-bicyclo[2.2.1]hep-tan, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(C-|-C4)-Alkyl, - C(O)-O-R11 , -(C<|-C4)-Alkyl-O-R11 oder Phenyl substituiert ist,13) - (C 0 -C 4 ) -alkylene-C (R 11) (R 12) -C (O) -O-R 11, or 14) - (C 1 -C 3 ) -fluoroalkyl, or the two radicals R 6 together with the N-atom to which they are attached form a mono- or bicyclic ring selected from the group of pyrrolidine, piperidine, 2-azabicyclo [3.2.2] nonane and 7-azabicyclo [2.2.1] heptene where the ring is unsubstituted or monosubstituted or disubstituted by - (C 1 -C 4) -alkyl, -C (O) -O-R 11, - (C 1 -C 4) -alkyl-O-R 11 or phenyl .
R7 für Wasserstoffatom oder -(C-|-C4)-Alkyl steht, R9 für Wasserstoffatom oder -(C-|-C4)-Alkyl steht,R7 is hydrogen atom or - (C- | -C4) alkyl, R9 is hydrogen atom or - (C- | -C4) -alkyl,
R11 und R12 gleich oder verschieden sind und unabhängig voneinander für 1) Wasserstoffatom, 2) -(C-i-C^-Alkyl,R 11 and R 12 are identical or different and independently of one another represent 1) hydrogen, 2) - (C 1 -C 4) -alkyl,
3) -(Crj-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch -OH, Halogen oder -O-(C<i-C4)-Alkyl substituiert ist,3) - (Cr j-C4) alkylene-phenyl, where phenyl is unsubstituted or independently mono-, di- or trisubstituted independently by -OH, halogen or -O- (C <i-C4) alkyl,
4) -(Co-C4)-Alkylen-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adamantanyl,4) - (Co-C4) -alkylene- (C3-C12) -cycloalkyl, where cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl,
1 ,7,7-Trimethyl-bicyclo[3.1.1]heptanyl, Decahydro-naphthalenyl, Tetrahydronaphthalenyl, Octahydro-4,7-methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch -(Ci-C4)-Alkyl, -C(O)-O-RI 3 oder Phenyl substituiert ist, oder 1591, 7,7-trimethyl-bicyclo [3.1.1] heptanyl, decahydro-naphthalenyl, tetrahydronaphthalenyl, octahydro-4,7-methano-indenyl or bicyclo [2.2.1] heptanyl and wherein cycloalkyl is unsubstituted or independently one or two -, triply or quadruply substituted by - (Ci-C4) -alkyl, -C (O) -O-RI 3 or phenyl, or 159
5) -(Co-C4)-Alkylen-Indolyl, stehen, R13 für 1) Wasserstoffatom,5) - (Co-C4) -alkylene-indolyl, R13 is 1) hydrogen,
2) -(C-i-C^-Alkyl,2) - (C 1 -C 4) -alkyl,
3) -(Co-C4)-Alkylen-C(0)-O-R14, 4) -(C0-C4)-Alkylen-C(O)-R14 oder3) - (Co-C 4 ) -alkylene-C (O) -O-R 14, 4) - (C 0 -C 4 ) -alkylene-C (O) -R 14 or
5) -(Co-C4)-Alkylen-0-R14 steht, und5) - (Co-C4) -alkylene-0-R14, and
R14 für Wasserstoffatom, -(C<|-C4)-Alkyl, -NH2 oder -OH steht undR 14 is hydrogen, - (C 1 -C 4 ) -alkyl, -NH 2 or -OH and
R15 für Wasserstoffatom, -(C-|-C4)-Alkyl, -O-CF3, -NH2, -OH, -CF3 oderR 15 is hydrogen, - (C 1 -C 4 ) -alkyl, -O-CF 3, -NH 2, -OH, -CF 3 or
Halogen steht.Halogen is available.
14. Verbindung der Formel I gemäß der Ansprüche 11 bis 13, wobei R1 für 1) Wasserstoffatom oder14. A compound of formula I according to claims 11 to 13, wherein R 1 is hydrogen or
2) -(C<|-C4)-Alkyl, steht,2) - (C 1 -C 4) -alkyl,
R2 für 1) -(C-i-C6)-Alkylen-NH2, 2) -(C<|-C4)-Alkylen-Pyridyl-NH2,R2 is 1) - (Ci-C6) alkylene-NH 2, 2) - (C <| -C4) alkylene-pyridyl-NH 2,
3) -(Ci-C4)-Alkylen-Piperidinyl-NH2,3) - (C 1 -C 4) -alkylene-piperidinyl-NH 2,
4) -(C1-C4)-Alkylen-NH-C(=NH)-NH2,4) - (C 1 -C 4 ) -alkylene-NH-C (= NH) -NH 2,
5) -(C1-C6)-Alkylen-NH-C(=NHHCi-C4)-Alkyl,5) - (C 1 -C 6 ) -alkylene-NH-C (= NHHCi-C 4 ) -alkyl,
6) -(C-i-C4)-Alkylen-(C3-C6)-Cycloalkyl-NH2, 7) -(C1-C4)-Alkylen-O-NH-C(=NH)-NH2i 6) - (C 1 -C 4 ) -alkylene- (C 3 -C 6 ) -cycloalkyl-NH 2 , 7) - (C 1 -C 4 ) -alkylene-O-NH-C (= NH) -NH 2i
8) -(C<|-C6)-Alkylen-NH-C(O)-O-(Ci-C4)-Alkylen-Phenyl,8) - (C <| -C6) alkylene-NH-C (O) -O- (Ci-C 4) -alkylene-phenyl,
9) -(C1-C4)-Alkylen-NH-C(O)-(C1-C6)-Alkyl,9) - (C 1 -C 4 ) -alkylene-NH-C (O) - (C 1 -C 6 ) -alkyl,
10) -(C-|-C4)-Alkylen-Phenyl-NH2,10) - (C 1 -C 4) -alkylene-phenyl-NH 2 ,
11) -(C1-C4)-Alkylen-SO2-(C<|-C4)-Alkylen-NH2l oder 12) -(C1-C4)-Alkylen-S-(C1-C4)-Alkylen-NH2, steht,11) - (C 1 -C 4) -alkylene-SO2- (C <| -C4) alkylene-NH 2l or 12) - (C 1 -C 4) alkylene-S- (C 1 -C 4) - Alkylene-NH2, is,
R3 für 1) -(C1-C4)-Alkyl,R 3 is 1) - (C 1 -C 4 ) -alkyl,
2) -(C1-C4)-Alkylen-(C3-C6)-Cycloalkyl,2) - (C 1 -C 4 ) -alkylene- (C 3 -C 6 ) -cycloalkyl,
3) -(C-|-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch - OH substituiert ist, 1603) - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or substituted by -OH, 160
4) -(Ci-C6)-Alkylen-NH-C(O)-O-(Ci-C4)-Alkylen-Phenyl,4) - (C 1 -C 6) -alkylene-NH-C (O) -O- (C 1 -C 4) -alkylene-phenyl,
5) Wasserstoffatom steht, R4 für -N(R6)2l steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander für 1) Wasserstoffatom,5) is hydrogen, R 4 is -N ( R 6 ) 2 l , where R 6 are identical or different and independently of one another represent 1) hydrogen atom,
2) -(C1-Ce)-AIkYl1 2) - (C 1 -Ce) alkyl 1
3) -(Co-C4)-Alkylen-(C3-C8)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclopropyl, Adamantanyl, 1 ,7,7- Trimethyl-bicyclo[3.1.1]heptanyl, Decahydro-naphthalen, Octahydro-4,7- methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch -(C-|-C4)-Alkyl oder Phenyl substituiert ist,3) - (C 1 -C 4) -alkylene- (C 3 -C 8) -cycloalkyl, where cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclopropyl, adamantanyl, 1, 7,7-trimethyl-bicyclo [3.1.1] heptanyl, Decahydro-naphthalene, octahydro-4,7-methano-indenyl or bicyclo [2.2.1] heptanyl and wherein cycloalkyl is unsubstituted or independently mono-, di- or trisubstituted by - (C 1 -C 4) -alkyl or phenyl .
4) -C(R11)(R12)-Adamantanyl,4) -C (R11) (R12) adamantanyl,
5) -CH(RI 1)-C(O)-NH-CH(R12)-R13, 6) -(Cn.-C4)-Alkylen-Het, wobei Het ausgewählt ist aus der Gruppe5) -CH (RI 1) -C (O) -NH-CH (R 12) -R 13, 6) - (C 1 -C 4) -alkylene-Het, wherein Het is selected from the group
Benzimidazolyl, Isoxazolyl, Piperidin, Pyridin, Pyrrolidinyl, Thiophenyl und Benzo[1 ,3]dioxol,Benzimidazolyl, isoxazolyl, piperidine, pyridine, pyrrolidinyl, thiophenyl and benzo [1,3] dioxole,
7) 1 ,2,3,4-Tetrahydro-naphthalenyl,7) 1, 2,3,4-tetrahydro-naphthalenyl,
8) -(Crj-C4)-Alkylen-C(R11 )(R12)-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch Phenyl oder Fluor substituiert ist,8) - (Crj-C4) -alkylene-C (R11) (R12) -phenyl, where phenyl is unsubstituted or independently of one another monosubstituted, disubstituted or trisubstituted by phenyl or fluorine,
9) -CH(RH)-C(O)-NH2,9) -CH (RH) -C (O) -NH 2 ,
10) -CH(RI 1)-C(O)-NH-CH(R12)-CH2-OH,10) -CH (RI 1) -C (O) -NH-CH (R 12) -CH 2 -OH,
11) -(Ci-C6)-Alkylen-Phenyl, wobei Phenyl oder Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Chlor, Fluor,11) - (C 1 -C 6) -alkylene-phenyl, where phenyl or alkylene is unsubstituted or independently of one another by chlorine, fluorine,
-C(O)-O-RH , -(C-|-C4)-Alkyl-O-R11 , -O-(C<|-C4)-AlkyI, Phenyl oder-C (O) -O-RH, - (C 1 -C 4 ) -alkyl-O-R 11, -O- (C 1 -C 4 ) -alkyl, phenyl or
-(Ci-C4)-Alkyl substituiert sind,- (C 1 -C 4) -alkyl are substituted,
12) -CH(RI I)-C(O)-N H-(C -i -C4)-Alkyl, 16112) -CH (RI 1) -C (O) -N H- (C 1 -C 4 ) -alkyl, 161
13) -(Co-C4)-Alkylen-C(R11)(R12)-Bicyclo[3.1.1]heptanyl, wobei13) - (Co-C4) -alkylene-C (R11) (R12) -bicyclo [3.1.1] heptanyl, wherein
Bicyclo[3.1.1]heptanyl unsubstituiert oder ein- bis vierfach durch -(C-|-C4)-Alkyl substituiert ist,Bicyclo [3.1.1] heptanyl is unsubstituted or substituted one to four times by - (C 1 -C 4) -alkyl,
14) -(C-|-C6)-Alkylen-C(O)-O-R11 , wobei Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Chlor, Fluor, -C(O)-O-R11 , -14) - (C 1 -C 6) -alkylene-C (O) -O-R 11, where alkylene is unsubstituted or independently of one another by chlorine, fluorine, -C (O) -O-R 11, -
(Ci-C4)-Alkyl-O-R11 , -O-(C<|-C4)-Alkyl, Phenyl oder -(C-|-C4)-Alkyl substituiert ist,(C 1 -C 4 ) -alkyl-O-R 11, -O- (C 1 -C 4 ) -alkyl, phenyl or - (C 1 -C 4 ) -alkyl,
15) -(Co-C4)-Alkylen-C(R11 )(R12)-C(O)-O-R11 , oder15) - (Co-C 4) -alkylene-C (R11) (R12) -C (O) -O-R11, or
16) -CH2-CF2-CF3, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom an das sie gebunden sind einen Mono- oder Bicyclischen Ring bilden, ausgewählt aus der Gruppe Pyrrolidine, 2-aza-bicyclo[3.2.2]nonan und 7-aza-bicyclo[2.2.1]heptan, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(C-(-C4)-Alkyl,16) -CH2-CF2-CF3, or the two radicals R6 together with the N-atom to which they are attached form a mono- or bicyclic ring selected from the group consisting of pyrrolidines, 2-aza-bicyclo [3.2.2 ] nonane and 7-aza-bicyclo [2.2.1] heptane, where the ring is unsubstituted or mono- or disubstituted by - (C - (- C4) -alkyl,
-C(O)-O-RH , -(C<|-C4)-Alkyl-O-R11 oder Phenyl substituiert ist, R7 f ür Wasserstoffatom oder -(C 1 -C4)-Alkyl steht,-C (O) -O-RH, - (C <| -> C4) -alkyl-O-R11 or phenyl, R7 stands for hydrogen atom or - (C 1 -C 4) -alkyl,
R9 für Wasserstoffatom oder -(C-|-C4)-Alkyl steht,R 9 is hydrogen or - (C 1 -C 4) -alkyl,
R11 und R12 gleich oder verschieden sind und unabhängig voneinander fürR11 and R12 are the same or different and independently of each other
1 ) Wasserstoffatom ,1) hydrogen atom,
2) -(C-i-C^-Alkyl, 3) -(Cn.-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch -OH, Halogen oder -O-(C-|-C4)-Alkyl substituiert ist,2) - (C 1 -C 4 -alkyl, 3) - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or independently mono-, di- or trisubstituted by -OH, halogen or -O- (C- | C4) -alkyl is substituted,
4) -(Co-C4)-Alkylen-(C3-Ci2)-Cyc|oa|ky'. wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adaman- tanyl, 1 ,7,7-Trimethyl-bicyclo[3.1.1Jheptanyl, Decahydro-naphthalenyl,4) - (Co-C4) -alkylene- (C3-Ci2) - C y c | o a | k y '. where cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, 1, 7,7-trimethyl-bicyclo [3.1.1heptanyl, decahydro-naphthalenyl,
Octahydro-4,7-methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch -(Ci-C4)-Alkyl, -C(O)-O-RI 3 oder Phenyl substituiert ist, oderOctahydro-4,7-methanoindenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently of one another mono-, di-, tri- or tetra-substituted by - (C 1 -C 4) -alkyl, -C (O) - O-RI 3 or phenyl, or
5) -(Crj-C4)-Alkylen-Indolyl, stehen, R13 für 1) Wasserstoffatom, 1625) - (C 1 -C 4) -alkylene-indolyl, R 13 is 1) hydrogen, 162
2) -(C1-C4J-AIKyI1 2) - (C 1 -C 4 -alkyl ) 1
3) -(C0-C4)-Alkylen-C(O)-O-R14,3) - (C 0 -C 4 ) -alkylene-C (O) -O-R 14,
4) -(C0-C4)-Alkylen-C(O)-R14 oder4) - (C 0 -C 4 ) -alkylene-C (O) -R 14 or
5) -(C0-C4)-Alkylen-O-R14 steht, R14 für Wasserstoffatom, -(Ci-C4)-Alkyl, -NH2 oder -OH steht und5) - (C 0 -C 4) -alkylene-O-R14, R14 is hydrogen, - (Ci-C 4) alkyl, -NH 2 or -OH and
R15 für Wasserstoffatom, -(Ci-C4)-Alkyl, -0-CF3, -NH2, -OH, -CF3 oder Halogen steht.R 15 is hydrogen, - (C 1 -C 4 ) -alkyl, -O-CF 3 , -NH 2, -OH, -CF 3 or halogen.
15. Verbindung der Formel I gemäß einem oder mehreren der Ansprüche 11 bis 14, dadurch gekennzeichnet, dass es die Verbindung der Formel I15. A compound of formula I according to one or more of claims 11 to 14, characterized in that it is the compound of formula I
(S)-6-Amino-2-(3-{(S)-1 -[(S)-1 -((S)-1 -methoxycarbonyl-2-methyl-propylcarb- amoyl)-2-methyl-propylcarbamoyl]-2-phenyl-ethyl}-sulfamidyl)-hexansäure, (S)- 6-Amino-2-{3-[(R)-1-(bicyclo[2.2.1]hept-2-ylcarbamoyl)-2-cyclohexyl-ethyl]- sulamidyl}-hexansäure, (S)-6-Amino-2-[3-((S)-1-cyclohexylcarbamoyl-2-phenyl- ethyl)-sulfamidyl]-hexansäure, (S)-6-Acetimidoylamino-2-{[(S)-2-cyclohexyl-1-(S) -6-Amino-2- (3 - {(S) -1 - [(S) -1 - ((S) -1-methoxycarbonyl-2-methyl-propylcarbamoyl) -2-methyl-propylcarbamoyl ] -2-phenylethyl} sulfamidyl) hexanoic acid, (S) -6-amino-2- {3 - [(R) -1- (bicyclo [2.2.1] hept-2-ylcarbamoyl) -2- cyclohexyl-ethyl] -sulamidyl} -hexanoic acid, (S) -6-amino-2- [3 - ((S) -1-cyclohexylcarbamoyl-2-phenylethyl) sulfamidyl] -hexanoic acid, (S) -6- Acetimidoylamino-2 - {[(S) -2-cyclohexyl-1-
((1 R,2S,4R)-1 ,7,7-trimethyl-bicyclo[2.2.1 ]hept-2-ylcarbamoyl)-ethylsulfamidyl]}- hexansäure, 3-(6-Amino-pyhdin-3-yl)-2-[(S)-2-cyclohexyl-1 -((1 R,2S,4R)-1 ,7,7- trimethyl-bicyclo^^.ilhept^-ylcarbamoyO-ethylsulfamid-yl]- propionsäureethylester, (S)-6-Amino-2-{[(S)-1-((1 R,2S,4R)-1 ,7,7-trimethyl- bicyclo^^.iJhept^-ylcarbamoyO-propylsulfamidylJ-J-hexansäure, (S)-2-{[(S)-2-((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-ylcarbamoyl) -ethylsulfamidyl] -hexanoic acid, 3- (6-amino-pyhindin-3-yl) -2 - [(S) -2-cyclohexyl-1 - ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo ^^. Ilhept ^ -ylcarbamoyO-ethylsulfamido-yl] -propionic acid ethyl ester, (S. ) -6-Amino-2 - {[(S) -1 - ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo] -alkyi} -hexyl-1-carbamoyl-O-propylsulfamidyl-J-hexanoic acid, ( S) -2 - {[(S) -2-
Cyclohexyl-1-((1R,2S,4R)-1 ,7,7-trimethyl-bicycio[2.2.1]hept-2-ylcarbamoyl)- ethylsulfamidyl]-}-5-guanidino-pentansäure, (S)-6-Amino-2-{[(S)-2-cyclobutyl-1- ((1 R,2S,4R)-1 ,7,7-trimethyl-bicyclo[2.2.1 ]hept-2-ylcarbamoyl)-ethylsulf-amidyl]}- hexansäure, (S)-5-Amino-2-({2-cyclohexyl-1 -[(R)-(1 , 2,3,4-tetrahydro- naphthalen-2-yl)carbamoyl]-ethylsulfamidyl})-pentansäure, (S)-2-{[(S)-2-Cyclohexyl-1 - ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-ylcarbamoyl) ethylsulfamidyl] -5-guanidino-pentanoic acid, (S) -6 -Amino-2 - {[(S) -2-cyclobutyl-1- ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-ylcarbamoyl) -ethylsulfonate amidyl]} - hexanoic acid, (S) -5-amino-2 - ({2-cyclohexyl-1 - [(R) - (1, 2,3,4-tetrahydronaphthalen-2-yl) carbamoyl] ethylsulfamidyl }) - pentanoic acid, (S) -2 - {[(S) -2-
Cyclohexyl-1-((1 R,2S,4R)-1 ,7,7-trimethyl-bicyclo[2.2.1]hept-2-ylcarbamoyl)- ethylsulfamidyl]}-6-hexanoylamino-hexansäure-ethylester, (S)-6-Amino-2-{[(S)- 1-((1 R,2S,4R)-1 ,7,7-trimethyl-bicyclo[2.2.1]hept-2-ylcarbamoyl)- butylsulfamidyl]}-hexansäure, (S)-6-Amino-2-{[(S)-3-cyclohexyl-1 -((1 R,2S,4R)- 1 ,7,7-trimethyl-bicyclo[2.2.1]hept-2-ylcarbamoyl)-propylsulf-amidyl]-methyl}- hexansäure, (S)-6-Amino-2-{[(S)-2-cyclohexyl-1-(decahydro-naphthalen-2- 163Cyclohexyl-1 - ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-ylcarbamoyl) ethylsulfamidyl] -6-hexanoylamino-hexanoic acid ethyl ester, (S) -6-amino-2 - {[(S) -1 - ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-ylcarbamoyl) -butylsulfamidyl]} - hexanoic acid, (S) -6-amino-2 - {[(S) -3-cyclohexyl-1 - ((1R, 2S, 4R) -1,7,7-trimethyl-bicyclo [2.2.1] hept- 2-ylcarbamoyl) -propylsulf-amidyl] -methyl} -hexanoic acid, (S) -6-amino-2 - {[(S) -2-cyclohexyl-1- (decahydro-naphthalene-2-yl) 163
ylcarbamoyl)-ethylsulfamidyl]}-hexansäure, (S)-2-{[(S)-1 -(Adamantan-1 - ylcarbamoyO^-cyclohexyl-ethylsulfamidyllJ-β-amino-hexan-säure, (S)-2-[(S)-2- Cyclohexyl-1-((1 R,2S,4R)-1 ,7,7-trimethyl-bicyclo[2.2.1]-hept-2-ylcarbamoyl)- ethylsulfamidyl]-3-pyridin-3-yl-propionsäure, (S)-2-[(S)-2-Cyclohexyl-1- ((1 R,2S,4R)-1 ,7,7-trimethyl-bicyclo[2.2.1 ]hept-2-ylcarbamoyl)-ethylsulfamidyl]-3- pyridin-4-yl-propionsäure, (S)-6-Amino-2-{[(S)-2-cyclohexyl-1 -((1 S,2S,3S,5R)- 2,6,6-trimethyl-bicyclo[3.1.1 ]hept-3-ylcarbamoyl)-ethylsulfamidyl]}-hexansäure, (S)-6-Amino-2-{[(S)-2-cyclohexyl-1-(3,3,5-trimethyl-cyclohexylcarbamoyl)- ethylsulfamidyl]}-hexansäure, (S)-6-Amino-2-{[(S)-1-(4-tert-butyl- cyclohexylcarbamoyl)-2-cyclohexyl-ethylsulfamidyl]}-hexansäure, (S)-6-Amino-ylcarbamoyl) ethylsulfamidyl]} - hexanoic acid, (S) -2 - {[(S) -1 - (adamantan-1-ylcarbamoyl) -cyclohexyl-ethylsulfamidyl-β-amino-hexanoic acid, (S) -2- [ (S) -2-Cyclohexyl-1 - ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] -hept-2-ylcarbamoyl) ethylsulfamidyl] -3-pyridine-3 -yl-propionic acid, (S) -2 - [(S) -2-cyclohexyl-1- ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-one ylcarbamoyl) ethylsulfamidyl] -3-pyridin-4-yl-propionic acid, (S) -6-amino-2 - {[(S) -2-cyclohexyl-1 - ((1S, 2S, 3S, 5R) - 2,6,6-trimethyl-bicyclo [3.1.1] hept-3-ylcarbamoyl) -ethylsulfamidyl] -hexanoic acid, (S) -6-amino-2 - {[(S) -2-cyclohexyl-1-one 3,3,5-trimethylcyclohexylcarbamoyl) ethylsulfamidyl] -hexanoic acid, (S) -6-amino-2 - {[(S) -1- (4-tert-butylcyclohexylcarbamoyl) -2-cyclohexylethylsulfamidyl ]} - hexanoic acid, (S) -6-amino
2-{[(S)-2-cyclohexyl-1-(3-methyl-cyclohexylcarbamoyl)-ethylsulfamidyl]}- hexansäure, (S)-6-Amino-2-{[(S)-2-cyclohexyl-1-((1 R,2S,4R)-1 ,7,7-trimethyl- bicyclo^^.ilhept^-ylcarbamoyO-ethylsulfamidylD-hexansäure, 3-(6-Amino- pyridin-3-ylmethyl)-2-[(S)-2-cyclohexyl-1-((1R,2S,4R)-1 ,7,7-trimethyl- bicyclo^^.iJhept^-yl-carbamoyO-ethylsulfamidylJ-propionsäure, 2-[(S)-2-2 - {[(S) -2-cyclohexyl-1- (3-methyl-cyclohexylcarbamoyl) -ethylsulfamidyl] -hexanoic acid, (S) -6-amino-2 - {[(S) -2-cyclohexyl-1] ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo) -benhexyl-1-carbamoyl-ethylsulfamidyl-D-hexanoic acid, 3- (6-aminopyridin-3-ylmethyl) -2 - [(S. ) -2-cyclohexyl-1 - ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo) -I-heptyl-carbamoyl-ethyl-sulfamidyl-1-propionic acid, 2 - [(S) -2-
Cyclohexyl-1-((1 R,2S,4R)-1 ,7,7-trimethyl-bicyclo[2.2.1]hept-2-ylcarbamoyl)- ethylsulfamidyl]-3-piperidin-4-yl-propionsäure, (S)-3-(4-Amino-phenyl)-2-[(S)-2- cyclohexyl-1 -((1 R,2S,4R)-1 ,7,7-trimethyl-bicyclo[2.2.1 ]hept-2-ylcarbamoyl)- ethylsulfamidyl]-propionsäure, (S)-6-Amino-2-[((S)-1-cyclohexylmethyl-2-oxo-2- piperidin-1 -yl-ethylsulfamidyl)]-hexansäure, (S)-5-Amino-2-{[(S)-2-cyclohexyl-1 -Cyclohexyl-1 - ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-ylcarbamoyl) ethylsulfamidyl] -3-piperidin-4-yl-propionic acid, (S. ) -3- (4-Amino-phenyl) -2 - [(S) -2-cyclohexyl-1 - ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept -2-ylcarbamoyl) ethylsulfamidyl] -propionic acid, (S) -6-amino-2 - [((S) -1-cyclohexylmethyl-2-oxo-2-piperidin-1-yl-ethylsulfamidyl)] - hexanoic acid, ( S) -5-amino-2 - {[(S) -2-cyclohexyl-1 -
((1 R,2S,4R)-1 ,7,7-trimethyl-bicyclo[2.2.1]hept-2-ylcarbamoyl)-ethylsulfamidyl]}- pentansäure, (S)-6-Amino-2-{[(S)-2-cyclohexyl-1 -((S)-1 -isobutylcarbamoyl-2- methyl-propylcarbamoyl)-ethylsulfamidyl]}-hexansäure (S)-6-Amino-2-{[(S)-1-((S)-1-isobutylcarbamoyl-2-methyl-propylcarbamoyl)-2- phenyl-ethylsulfamidyl]}-hexansäure, (S)-6-Amino-2-[((S)-2-cyclohexyl-1- isobutylcarbamoyl-ethylsulfamidyl)]-hexansäure, (S)-6-Amino-2-{[(S)-1- ((1 R,2R,4S)-bicyclo[2.2.1]hept-2-ylcarbamoyl)-2-cyclohexyl-ethylsulfamidyl]}- hexansäure, (S)-6-Amino-2-{[(S)-2-cyclohexyl-1 -((1 R,2S,4R)-1 ,7,7-trimethyl- bicyclo^^.ijhept^-ylcarbamoylj-ethylsulfamidyljj-hexansäure, (S)-6-Amino-2- {[(S)-1-((1 S,4R)-bicyclo[2.2.1 ihept^-ylcarbamoyO^-cyclohexyl-ethylsulf- amidyl]}-hexansäure, (S)-6-Amino-2-{[(S)-2-cyclohexyl-1-(octahydro-4,7- methano-inden-5-ylcarbamoyl)-ethylsulfamidyl]}-hexansäure, (S)-6-Amino-2- 164((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-ylcarbamoyl) ethylsulfamidyl] -pentanoic acid, (S) -6-amino-2 - {[( S) -2-cyclohexyl-1 - ((S) -1-isobutylcarbamoyl-2-methyl-propylcarbamoyl) -ethylsulfamidyl] -hexanoic acid (S) -6-amino-2 - {[(S) -1 - (( S) -1-isobutylcarbamoyl-2-methyl-propylcarbamoyl) -2-phenylethylsulfamidyl] -hexanoic acid, (S) -6-amino-2 - [((S) -2-cyclohexyl-1-isobutylcarbamoyl-ethylsulfamidyl) ] -hexanoic acid, (S) -6-amino-2 - {[(S) -1- ((1R, 2R, 4S) -bicyclo [2.2.1] hept-2-ylcarbamoyl) -2-cyclohexylethylsulfamidyl ]} - hexanoic acid, (S) -6-amino-2 - {[(S) -2-cyclohexyl-1 - ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo] -benzene ^ -ylcarbamoylj-ethylsulfamidyljj-hexanoic acid, (S) -6-amino-2- {[(S) -1 - ((1S, 4R) -bicyclo [2.2.1 ihept ^ -ylcarbamoyO] -cyclohexyl-ethylsulfamidamide ]} - hexanoic acid, (S) -6-amino-2 - {[(S) -2-cyclohexyl-1- (octahydro-4,7-methanoinden-5-ylcarbamoyl) -ethylsulfamidyl] -hexanoic acid, ( S) -6-amino-2- 164
[((SJ-i-tert-butylcarbamoyl^-cyclohexyl-ethylsulfamidyOl-hexansäure, (S)-2- {[(S)-1 -(Adamantan-1 -ylcarbamoyl)-2-phenyl-ethylsulfamidyl]}-6-amino- hexansäure, (S)-6-Amino-2-{[(S)-1-((1S,4R)-bicyclo[2.2.1]hept-2-ylcarbamoyl)- 2-phenyl-ethylsulfamidyl]}-hexansäure, (S)-2-{[(S)-1 -(Adamantan-1 - ylcarbamoyl)-2-(4-hydroxy-phenyl)-ethylsulfamidyl]}-6-amino-hexansäure, (S)-6-[((SJ-i-tert-butylcarbamoyl-cyclohexyl-ethylsulfamido-O-hexanoic acid, (S) -2- {[(S) -1 - (adamantane-1-ylcarbamoyl) -2-phenyl-ethylsulfamidyl]} - 6- aminohexanoic acid, (S) -6-amino-2 - {[(S) -1 - ((1S, 4R) -bicyclo [2.2.1] hept-2-ylcarbamoyl) -2-phenylethylsulfamidyl]} - hexanoic acid, (S) -2 - {[(S) -1 - (adamantan-1-ylcarbamoyl) -2- (4-hydroxyphenyl) ethylsulfamidyl]} - 6-aminohexanoic acid, (S) -6-
Amino-2-{[(S)-2-phenyl-1-((1 R,2S,4R)-1 ,7,7-trimethyl-bicyclo[2.2.1]hept-2- ylcarbamoyl)-ethylsulfamidyl]}-hexansäure, (S)-6-Amino-2-({[(S)-cyclohexyl- (1 ,7,7-trimethyl-bicyclo[2.2.1 ]hept-2-ylcarbamoyl)-methyl]-sulfamidyl})- hexansäure, (S)-6-Amino-2-{[(S)-2-cyclohexyl-1 -((1 R,2R,4R)-1 ,7,7-trimethyl- bicyclo[2.2.1 ]hept-2-ylcarbamoyl)-ethylsulfamidyl]}-hexansäure, (S)-6-Amino-2-Amino-2 - {[(S) -2-phenyl-1 - ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-ylcarbamoyl) -ethylsulfamidyl]} hexanoic acid, (S) -6-amino-2 - ({[(S) -cyclohexyl- (1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-ylcarbamoyl) -methyl] -sulfamidyl}) - hexanoic acid, (S) -6-amino-2 - {[(S) -2-cyclohexyl-1 - ((1R, 2R, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept -2-ylcarbamoyl) -ethylsulfamidyl] -hexanoic acid, (S) -6-amino-2-yl
{[(S)-2-cyclopropyl-1-((1R,2R,4R)-1 ,7,7-trimethyl-bicyclo[2.2.1]hept-2- ylcarbamoyl)-ethylsulfamidyl]}-hexansäure, (S)-6-Amino-2-{[(S)-2-cyclohexyl-1- (3,5-dimethyl-adamantan-1-ylcarbamoyl)-ethylsulf-amidyl]}-hexansäure, (S)-6- Amino-2-{[(S)-2-cyclohexyl-1-(3-isopropyl-adamantan-1-ylcarbamoyl)- ethylsulfamidyl]}-hexansäure, (S)-6-Amino-2-{[(S)-2-cyclohexyl-1 -((1 R,2R,4R)-{[(S) -2-cyclopropyl-1 - ((1R, 2R, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-ylcarbamoyl) -ethylsulfamidyl] -hexanoic acid, (S. ) -6-amino-2 - {[(S) -2-cyclohexyl-1- (3,5-dimethyl-adamantan-1-ylcarbamoyl) -ethylsulfamido] -hexanoic acid, (S) -6-amino- 2 - {[(S) -2-cyclohexyl-1- (3-isopropyl-adamantan-1-ylcarbamoyl) -ethylsulfamidyl] -hexanoic acid, (S) -6-amino-2 - {[(S) -2- cyclohexyl-1 - ((1R, 2R, 4R) -
1 ,7,7-trimethyl-bicyclo[2.2.1 ]hept-2-ylcarbamoyl)-ethylsulfamidyl]}-hexansäure- tert-butylester oder (S)-2-{[(S)-1 -(Adamantan-1 -ylcarbamoyl)-3-methyl- butylsulfamidyl]}-6-amino-hexansäure ist.1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-ylcarbamoyl) ethylsulfamidyl] -hexanoic acid tert-butyl ester or (S) -2 - {[(S) -1- (adamantane-1-one ylcarbamoyl) -3-methyl-butylsulfamidyl]} - 6-amino-hexanoic acid.
16. Verbindung der Formel16. Compound of the formula
Figure imgf000166_0001
und/oder einer stereoisomeren Form der Verbindung der Formel I und/oder Gemische dieser Formen in jedem Verhältnis, und/oder ein physiologisch verträgliches Salz der Verbindung der Formel I, wobei X für -C(O)- steht,
Figure imgf000166_0001
and / or a stereoisomeric form of the compound of the formula I and / or mixtures of these forms in any ratio, and / or a physiologically acceptable salt of the compound of the formula I in which X is -C (O) -,
R1 für 1) Wasserstoff atom,R1 for 1) hydrogen atom,
2) -(C1-Ce)-AIKyI,2) - (C 1 -Ce) -Alkyl,
3) -(Crj-C4)-Alkylen-(C3-Ci2)-Cycloalkyl oder3) - (Crj-C4) -alkylene- (C3-Ci2) -cycloalkyl or
4) -(C1 -C6)-Alkylen-(C6-C 14)-Aryl steht, 1654) - (C 1 -C 6) alkylene- (C6-C14) -aryl, 165
R2 für den Rest der Formel IlR2 for the rest of Formula II
-(A1)m-A2 (II) steht, worin m die ganze Zahl Null oder 1 bedeutet, A1 für 1) -(CH2)rr- worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet,- (A1) m -A2 (II), where m is the integer zero or 1, A1 is 1) - (CH 2) r r - where n is the integer zero, 1, 2 or 3,
2) -NH-(CH2)n-, worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet,2) -NH- (CH 2) n -, where n is the integer zero, 1, 2 or 3,
3) -NH(Ci-C6)-Alkyl)-(CH2)n-, worin n die ganze Zahl Null, 1, 2 oder 3 bedeutet,3) -NH (C 1 -C 6 ) -alkyl) - (CH 2) n -, where n is the integer zero, 1, 2 or 3,
4) -NH((C3-C6)-Cycloalkyl)-(CH2)n-, worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet,4) -NH ((C 3 -C 6 ) -cycloalkyl) - (CH 2 ) n-, where n is the integer zero, 1, 2 or 3,
5) -O-(CH2)rr. worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet, oder5) -O- (CH 2) rr. where n is the integer zero, 1, 2 or 3, or
6) -(CH2)n-SOx-, worin n die ganze Zahl Null, 1 , 2 oder 3 bedeutet und x die ganze Zahl Null, 1 oder 2 bedeutet, steht, A2 für 1) Het, wobei unter Het ein 4- bis 15-gliedriges heterocyclisches6) - (CH 2) n-SO x -, wherein n is the integer zero, 1, 2 or 3 and x is the integer zero, 1 or 2, A2 is 1) Het, Het being a 4 - to 15-membered heterocyclic
Ringsystem mit 4 bis 15 Ringatomen verstanden wird, die in ein, zwei oder drei miteinander verbundenen Ringsystemen vorliegen und die ein, zwei, drei oder vier gleiche oder verschiedene Heteroatome aus der Reihe Sauerstoff, Stickstoff oder Schwefel enthalten und unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch ein -(C -|-Ring system comprising 4 to 15 ring atoms which are present in one, two or three interconnected ring systems and which contain one, two, three or four identical or different heteroatoms from the series oxygen, nitrogen or sulfur and are unsubstituted or independently of one another, two or three times by a - (C - | -
C3)-Alkyl, Halogen, -NH2, -CF3 oder -O-CF3 substituiert ist,C3) -alkyl, halogen, -NH2, -CF3 or -O-CF3 is substituted,
2) -(C0-C6)-Alkylen-NH2 ,2) - (C 0 -C 6 ) -alkylene-NH 2 ,
3) -(C1-C6)-Alkylen-NH-C(=NH)-NH2j 3) - (C 1 -C 6) alkylene-NH-C (= NH) -NH 2j
4) -(C1-C6)-Alkylen-NH-C(=NH)-(Ci-C4)-Alkyl, 5) -(C0-C4)-Alkylen-O-NH-C(=NH)-NH2i 4) - (C 1 -C 6) -alkylene-NH-C (= NH) - (Ci-C 4) -alkyl, 5) - (C 0 -C 4) -alkylene-O-NH-C (= NH ) -NH 2i
6) -(C0-C4)-Alkylen-NH-C(O)-(C1-C6)-Alkyl,6) - (C 0 -C 4 ) -alkylene-NH-C (O) - (C 1 -C 6 ) -alkyl,
7) -(C1 -C6)-Alkylen-NH-C(O)-O-(Ci -C4)-Alkylen-Aryl, wobei Aryl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist, 8) -(C3-C8)-Cycloalkyl-NH2, oder 1667) - (C 1 -C 6 ) -alkylene-NH-C (O) -O- (C 1 -C 4 ) -alkylene-aryl, where aryl is unsubstituted or substituted by -NH 2 or by -NH 2 and is substituted by R15 two or three times, 8) - (C3-C8) -cycloalkyl-NH2, or 166
9) -(C()-C4)-Alkylen-(C6-C"i4)-Aryl, wobei Aryl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist, steht, R3 für 1) -(C-|-C6)-Alkyl, 2) -(Co-C4)-Alkylen-(C3-C-|2)-Cycloalkyl,9) - (C () -C 4) -alkylene- (C 6 -C 14) -aryl, wherein aryl is unsubstituted or substituted by -NH 2 or substituted by -NH 2 and mono-, di- or trisubstituted by R 15 , R3 is 1) - (C- | -C6) alkyl, 2) - (Co-C4) -alkylene- (C3-C- | 2) cycloalkyl,
3) -(C-|-C6)-Alkylen-(C6-C-|4)-Aryl, wobei Aryl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,3) - (C- | -C6) alkylene- (C6-C- | 4) -aryl, wherein aryl is independently mono-, di- or trisubstituted by R15,
4) -(C0-C8)-Alkylen-N(R5)-PG,4) - (C 0 -C 8) -alkylene-N (R 5) -PG,
5) -(C^CeJ-Alkylen-NH-CCOJ-O-CC-i-C^-Alkylen-Aryl, wobei Aryl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,5) - (C 1 -C 6) -alkylene-NH-CCOJ-O-CC-C 1 -C 4 -alkylene aryl, where aryl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15,
6) -(Co-C4)-Alkylen-(C6-C14)-Aryl-(Co-C4)-Alkylen-N(R5)-PGI 6) - (C o -C 4 ) -alkylene- (C 6 -C 14) -aryl (C 1 -C 4 ) -alkylene-N (R 5) -PG I
7) -(C0-C8)-Alkylen-O-PG,7) - (C 0 -C 8 ) -alkylene-O-PG,
8) -(Co-C4)-Alkylen-(C6-C14)-Aryl-(Co-C4)-Alkylen-O-PG, 9) -(C0-C8)-Alkylen-C(O)-O-PG,8) - (Co-C4) alkylene- (C6-C14) aryl (Co-C4) -alkylene-O-PG, 9) - (C 0 -C 8) -alkylene-C (O) - O-PG,
10) -(C0-C4)-Alkylen-(C6-C14)-Aryl-(Co-C4)-Alkylen-C(O)-0-PG,10) - (C 0 -C 4 ) -alkylene- (C 6 -C 14 ) -aryl (C 1 -C 4 ) -alkylene-C (O) -O-PG,
11 ) Wasserstoff atom , steht, R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander für 1) Wasserstoff atom,11) hydrogen atom, R4 is -N (R6) 2, where R6 are the same or different and independently of one another represents 1) hydrogen atom,
2) -(C1-C6)-Alkyl,2) - (C 1 -C 6 ) -alkyl,
3) -(Co-C4)-Alkylen-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R11 , Halogen, -C(O)-O-RH , -(Ci-C4)-Alkyl-O-R11 oder -O-(C-|-C4)-Alkyl substituiert ist,3) - (Co-C4) -alkylene- (C3-C12) -cycloalkyl, where cycloalkyl is unsubstituted or independently of one another once, twice, three or four times by R11, halogen, -C (O) -O-RH, (C 1 -C 4) -alkyl-O-R 11 or -O- (C 1 -C 4) -alkyl,
4) -(Co-C6)-Alkylen-(C6-C-|4)-Aryl, wobei Aryl und Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R11 , Halogen, -C(O)-O-RH , -(Ci-C4)-Alkyl-O-R11 , -C(O)-N(R8)2 oder -O-(C-|-C4)-Alkyl substituiert sind, 1674) - (Co-C6) -alkylene- (C6-C- | 4) -aryl, where aryl and alkylene are unsubstituted or independently of one another once, twice, three or four times by R11, halogen, -C (O) -O-RH, - (C 1 -C 4) -alkyl-O-R 11, -C (O) -N (R 8) 2 or -O- (C 1 -C 4) -alkyl, 167
5) -(Co-C8)-Alkylen-N(R5)-PG,5) - (Co-C8) -alkylene-N (R5) -PG,
6) -(Co-C4)-Alkylen-(C6-C14)-Aryl-(Co-C4)-Alkyl-N(R5)-PG,6) - (Co-C 4 ) -alkylene- (C 6 -C 14 ) -aryl (Co-C 4 ) -alkyl-N (R 5) -PG,
7) -(Co-C8)-Alkylen-0-PG,7) - (Co-C8) -alkylene-0-PG,
8) -(Co-C4)-Alkylen-(C6-Ci4)-Aryl-(Co-C4)-Alkyl-0-PG, 9) -(Co-C8)-Alkylen-C(0)-0-R11 ,8) - (Co-C4) alkylene- (C6-Ci4) aryl (Co-C 4) alkyl-0-PG, 9) - (Co-C8) -alkylene-C (0) -0 -R11,
10) -(C0-C4)-Alkylen-(C6-C14)-Aryl-(Co-C4)-Alkyl-C(O)-O-PG,10) - (C 0 -C 4 ) -alkylene- (C 6 -C 14 ) -aryl (Co-C 4 ) -alkyl-C (O) -O-PG,
11) -(Co-C4)-Alkylen-Het, wobei unter Het ein 4- bis 15-gliedriges heterocyclisches Ringsystem verstanden wird mit 4 bis 15 Ringatomen, die in ein, zwei oder drei miteinander verbundenen Ringsystemen vorliegen und die ein, zwei, drei oder vier gleiche oder verschiedene Heteroatome aus der Reihe11) - (Co-C 4 ) -alkylene-Het, where Het is a 4- to 15-membered heterocyclic ring system is understood with 4 to 15 ring atoms, which are present in one, two or three interconnected ring systems and the one, two , three or four identical or different heteroatoms from the series
Sauerstoff, Stickstoff oder Schwefel enthalten, wobei Het oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-RH , -(C1 -C4)-Alkyl-O-R11 oder -0-(C1 -C4)-Alkyl substituiert sind, 12) -(C-i-CaJ-Fluoralkyl,In which Het or alkylene is unsubstituted or independently of one another mono-, di- or trisubstituted by R11, halogen, -C (O) -O-RH, - (C 1 -C 4 ) -alkyl-O-, R 11 or -O- (C 1 -C 4 ) -alkyl are substituted, 12) - (C 1 -C 10 -fluoroalkyl,
13) -(Crj-C4)-Alkylen-CH(R11 )-C(O)-NH2,13) - (Crj-C 4 ) -alkylene-CH (R 11) -C (O) -NH 2,
14) -(Co-C4)-Alkylen-CH(R11)-C(O)-NH-(Ci-C4)-Alkyl,14) - (Co-C4) -alkylene-CH (R11) -C (O) -NH- (C 1 -C 4) -alkyl,
15) -(Co-C4)-Alkylen-CH(R11 )-C(O)-NH-CH(R12)-R13, oder15) - (Co-C4) alkylene-CH (R11) -C (O) -NH-CH (R12) -R13, or
16) Aminosäure, wobei die Bindung der Aminosäure über eine Peptid- Bindung erfolgt und der Carboxyl-Rest der Aminosäure unsubstituiert oder durch PG oder durch -N(R5)2 substituiert ist, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom, an das sie gebunden sind, einen mono- oder bicyclischen Ring mit 4 bis 9 Ringatomen bilden, der gesättigt, teilweise gesättigt oder aromatisch ist, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(Ci-C4)-Alkyl, -C(O)-O-R11 ,16) amino acid, wherein the binding of the amino acid takes place via a peptide bond and the carboxyl radical of the amino acid is unsubstituted or substituted by PG or by -N (R5) 2, or the two radicals R6 together with the N-atom to which they are attached form a mono- or bicyclic ring having 4 to 9 ring atoms which is saturated, partially saturated or aromatic, the ring being unsubstituted or mono- or disubstituted by - (C 1 -C 4 ) -alkyl, C (O) -O-R11,
Halogen, -(C-|-C4)-Alkyl-O-R11 oder Phenyl substituiert ist, R5 für Wasserstoffatom oder-^ -CßJ-Alkyl steht,Halogen, - (C 1 -C 4) -alkyl-O-R 11 or phenyl, R 5 is hydrogen or C 1 -C 6 -alkyl,
PG füreine Schutzgruppe für die Amino-, Carboxyl- oder für die Hydroxyfunktion steht, R7 für Wasserstoffatom oder -(C-i-CßJ-Alkyl steht, 168PG is a protective group for the amino, carboxyl or for the hydroxyl function, R 7 is hydrogen or - (C 1 -C 6) -alkyl, 168
R8 für Wasserstoffatom oder -(C-|-C6)-Alkyl steht, R9 für Wasserstoffatom oder -(C-|-C6)-Alkyl steht,R 8 is hydrogen or - (C 1 -C 6) -alkyl, R 9 is hydrogen or - (C 1 -C 6) -alkyl,
R11 und R12 gleich oder verschieden sind und unabhängig voneinander für 1 ) Wasserstoffatom , 2) -(C1-Ce)-AIkYl,R 11 and R 12 are identical or different and independently of one another represent 1) hydrogen atom, 2) - (C 1 -C 6) -alkyl,
3) -(CQ-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder oder unabhängig voneinander ein-, zwei- oder dreifach durch Halogen, -OH oder -O-(Ci-C4)-Alkyl substituiert ist,3) - (CQ-C4) -alkylene-phenyl, where phenyl is unsubstituted or substituted independently of one another once, twice or three times by halogen, -OH or -O- (C 1 -C 4) -alkyl,
4) -(Crj-C4)-Alkylen-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R13,4) - (C 1 -C 4) -alkylene- (C 3 -C 12) -cycloalkyl, where cycloalkyl is unsubstituted or independently of one another once, twice, three or four times by R 13,
Halogen, -C(O)-O-RI 3, -(Ci-C4)-Alkyl-O-R13, -O-(C-|-C4)-Alkyl oderHalogen, -C (O) -O-RI 3, - (Ci-C4) -alkyl-O-R13, -O- (C- | -C4) alkyl or
-(Crj-C4)-Alkylen-Phenyl substituiert ist,- (Cr j-C4) alkylene-phenyl,
5) -(Co-C4)-Alkylen-C(O)-N(R13)2 oder5) - (Co-C 4 ) -alkylene-C (O) -N (R 13) 2 or
6) -(Cn-C4)-Alkylen-Indolyl, stehen, R13 für 1) Wasserstoffatom,6) - (C 1 -C 4) -alkylene-indolyl, R 13 is 1) hydrogen,
2) -(C1-C4J-AIkVl1 2) - (C 1 -C 4 J-AlkVl 1
3) -(Co-C4)-Alkylen-C(0)-0-R14,3) - (Co-C 4 ) -alkylene-C (O) -O-R 14,
4) -(Co-C4)-Alkylen-C(O)-R14 oder4) - (Co-C 4) -alkylene-C (O) -R 14 or
5) -(Co-C4)-Alkylen-O-R14 steht, R14 für Wasserstoff atom, -(C<|-C4)-Alkyl, -NH2 oder -OH, steht und5) - (Co-C 4) -alkylene-O-R14, R14 is hydrogen atom, - (C <| -C4) alkyl, -NH 2 or -OH, and is
R15 für Wasserstoffatom, -(Ci-C4)-Alkyl, -O-CF3, -NH2, -OH, -CF3 oder Halogen steht.R 15 is hydrogen, - (C 1 -C 4 ) -alkyl, -O-CF 3, -NH 2 , -OH, -CF 3 or halogen.
17. Verbindung der Formel I gemäß Anspruch 16, wobei R1 für 1) Wasserstoffatom oder17. A compound of formula I according to claim 16, wherein R1 is 1) hydrogen or
2) -(Ci-C4)-Alkyl, steht, R2 für 1) -(C1-C6)-Alkylen-NH2,2) - (C 1 -C 4 ) -alkyl, R 2 is 1) - (C 1 -C 6 ) -alkylene-NH 2 ,
2) -(Co-C4)-Alkylen-Pyridyl-NH2,2) - (Co-C 4 ) -alkylene-pyridyl-NH 2 ,
3) -(Co-C4)-Alkylen-Piperidinyl-NH2, 1693) - (Co-C4) -alkylene-piperidinyl-NH 2 , 169
4) -(C0-C4)-Alkylen-Thiazolyl-NH2,4) - (C 0 -C 4) -alkylene-thiazolyl-NH 2 ,
5) -(C1-C6)-Alkylen-NH-C(=NH)-NH2,5) - (C 1 -C 6) -alkylene-NH-C (= NH) -NH 2,
6) -(Co-C4)-Alkylen-(C3-C8)-Cycloalkyl-NH2,6) - (Co-C 4 ) -alkylene- (C 3 -C 8) -cycloalkyl-NH 2 ,
7) -(C1-C6)-Alkylen-NH-C(=NH)-(C1-C4)-Alkyl, 8) -(C0-C4)-Alkylen-O-NH-C(=NH)-NH2i 7) - (C 1 -C 6 ) -alkylene-NH-C (= NH) - (C 1 -C 4) -alkyl, 8) - (C 0 -C 4) -alkylene-O-NH-C (= NH ) -NH 2i
9) -(Ci-C6)-Alkylen-NH-C(O)-O-(Ci-C4)-Alkylen-Aryl, wobei Aryl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist,9) - (Ci-C6) alkylene-NH-C (O) -O- (Ci-C4) -alkylene-aryl, wherein aryl is unsubstituted or substituted by -NH 2 or -NH 2, and mono-, di- or is substituted by R15 in triplicate,
10) -(C0-C4)-Alkylen-N H-C(O)-(C -i-C4)-Alkyl, 11) -(Co-C4)-Alkylen-(C6-Ci4)-Aryl, wobei Aryl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist, oder10) - (C 0 -C 4 ) -alkylene-N HC (O) - (C 1 -C 4 ) -alkyl, 11) - (Co-C 4 ) -alkylene- (C 6 -C 14) -aryl, wherein aryl is unsubstituted or is substituted by -NH 2 or by -NH 2 and mono-, di- or trisubstituted by R 15, or
12) -(Ci-C4)-Alkylen-SOx-(C-|-C4)-Alkylen-NH2 worin x die ganze12) - (Ci-C4) alkylene-SO x - (C- | -C4) alkylene-NH 2 wherein x is the whole
Zahl Null, 1 oder 2 bedeutet, steht, R3 für 1) -(C<|-C4)-Alkyl,Number zero, 1 or 2, R 3 is 1) - (C 1 -C 4) -alkyl,
2) -(Co-C4)-Alkylen-(C3-C8)-Cycloalkyl,2) - (Co-C4) -alkylene- (C3-C8) -cycloalkyl,
3) -(C-|-C6)-Alkylen-Aryl, wobei Aryl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,3) - (C 1 -C 6) -alkylene-aryl, where aryl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15,
4) -(C-i-C6)-Alkylen-NH-C(O)-O-(Ci-C4)-Alkylen-Aryl, wobei Aryl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,4) - (C 1 -C 6) -alkylene-NH-C (O) -O- (C 1 -C 4 ) -alkylene-aryl, where aryl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15,
5) -(C1 -C6)-Alkylen-N H-PG,5) - (C 1 -C 6) -alkylene-N H-PG,
6) -(C-i-CöJ-Alkylen-O-PG,6) - (C 1 -C 6) -alkylene-O-PG,
7) -(C-ι-C6)-Alkyl, oder 8) Wasserstoff atom, steht, wobei PG für t-Butyl-, t-Butyloxycarbonyl oder Benzyloxycarbonyl steht, R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander für 1 ) Wasserstoffatom , 1707) - (C-ι-C 6 ) alkyl, or 8) hydrogen atom, wherein PG is t-butyl, t-butyloxycarbonyl or benzyloxycarbonyl, R4 is -N (R6) 2 , wherein R6 are the same or different and independently of one another represent 1) hydrogen atom, 170
2) -(C1-Ce)-AIkYl,2) - (C 1 -Ce) -Alkyl,
3) -(Co-C4)-Alkylen-(C3-C-|2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R11 , Halogen, -C(O)-O-RH , -(Ci-C4)-Alkyl-O-R11 oder -0-(C1 -C4)-Alkyl substituiert ist,3) - (Co-C4) -alkylene- (C3-C- | 2) -cycloalkyl, wherein cycloalkyl is unsubstituted or independently of one another once, twice, three or four times by R11, halogen, -C (O) -O -RH, - (Ci-C4) -alkyl-O-R11 or -0- (C 1 -C 4) -alkyl substituted,
4) -(C0-C4)-Alkylen-C(R11)(R12)-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-RH , -(C<|-C4)-Alkyl-O-R11 oder -0-(C1 -C4)-Alkyl substituiert ist, 5) -(Crj-C4)-Alkylen-Het, wobei unter Het ein 4- bis 15-gliedriges heterocyclisches Ringsystem verstanden wird mit 4 bis 15 Ringatomen, die in ein, zwei oder drei miteinander verbundenen Ringsystemen vorliegen und die ein, zwei, drei oder vier gleiche oder verschiedene Heteroatome aus der Reihe Sauerstoff, Stickstoff oder Schwefel enthalten, wobei Het oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch4) - (C 0 -C 4 ) -alkylene-C (R 11) (R 12) - (C 3 -C 12) -cycloalkyl, where cycloalkyl is unsubstituted or independently of one another mono-, di- or trisubstituted by R 11, halogen, -C ( O) -O-H, - (C <| -C4) alkyl-O-R11 or -0- (C 1 -C 4) alkyl substituted 5) - (Cr j -C 4) alkylene -Het, wherein Het is a 4- to 15-membered heterocyclic ring system is understood with 4 to 15 ring atoms, which are present in one, two or three interconnected ring systems and the one, two, three or four identical or different heteroatoms from the series Contain oxygen, nitrogen or sulfur, wherein Het or alkylene unsubstituted or independently of one, two or three times by
R11 , Halogen, -C(O)-O-RH , -(C-i-C^-Alkyl-O-RH oder -0-(C1 -C4)-Alkyl substituiert sind,R 11, halogen, -C (O) -O-RH, - (C 1 -C 4 -alkyl-O-RH or -O- (C 1 -C 4 ) -alkyl,
6) -(Crj-Ce)-Alkylen-Aryl, wobei Aryl oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-R11 , -(Co-C4)-Alkyl-O-R11 oder -O-(C-|-C4)-Alkyl substituiert sind,6) - (Crj-Ce) -alkylene-aryl, where aryl or alkylene are unsubstituted or independently of one another mono-, di- or trisubstituted by R 11, halogen, -C (O) -O-R 11, - (Co-C 4 ) alkyl-O-R11 or -O- (C- | -C4) alkyl substituted,
7) -(C0-C4)-Alkylen-C(R11 )(R12)-Aryl, wobei Aryl oder Alkylen unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch R11 , Halogen, -C(O)-O-RH , -(C0-C4)-Alkyl-O-R11 oder -0-(C1 -C4)-Alkyl substituiert sind, 8) 1 ,2,3,4-Tetrahydro-naphthalenyl,7) - (C 0 -C 4 ) -alkylene-C (R 11) (R 12) -aryl, wherein aryl or alkylene are unsubstituted or independently of one another mono-, di- or trisubstituted by R 11, halogen, -C (O) -O -RH, - (C 0 -C 4 ) -alkyl-O-R 11 or -O- (C 1 -C 4 ) -alkyl, 8) 1, 2,3,4-tetrahydro-naphthalenyl,
9) -(C0-C4)-Alkylen-CH(R11 )-C(O)-NH2,9) - (C 0 -C 4) alkylene-CH (R11) -C (O) -NH 2,
10) -(C0-C4)-Alkylen-CH(R11)-C(O)-NH-(C <|-C4)-Alkyl,10) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH- (C 1 -C 4 ) -alkyl,
11) -(C0-C4)-Alkylen-CH(R11)-C(O)-NH-CH(R12)-R13, 17111) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH-CH (R 12) -R 13, 171
12) -(Co-C6)-Alkylen-C(O)-0-R11 , wobei Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch R11 , Halogen, -C(O)-O-RH , -(C<|-C4)-Alkyl-O-R11 oder -O-(C-|-C4)-Alkyl substituiert ist,12) - (Co-C6) -alkylene-C (O) -O-R11, wherein alkyls are unsubstituted or independently of one another once or twice by R11, halogen, -C (O) -O-RH, - (C < -C 4) -alkyl-O-R 11 or -O- (C 1 -C 4) -alkyl,
13) -(Cn-C4)-Alkylen-C(R11 )(R12)-C(O)-O-R11 , oder 14) -(C-|-C3)-Fluoralkyl, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom, an das sie gebunden sind, einen mono- oder bicyclischen Ring mit 4 bis 9 Ringatomen bilden, der gesättigt, teilweise gesättigt oder aromatisch ist, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(Ci-C4)-Alkyl, -C(O)-O-R11, Halogen, -(C-|-C4)-Alkyl-O-R11 oder Phenyl substituiert ist,13) - (Cn-C4) -alkylene-C (R11) (R12) -C (O) -O-R11, or 14) - (C- | -C3) -fluoroalkyl, stand, or the two radicals R6 together with the N atom to which they are attached form a mono- or bicyclic ring having 4 to 9 ring atoms which is saturated, partially saturated or aromatic, the ring being unsubstituted or mono- or disubstituted by - (Ci-C4 ) -Alkyl, -C (O) -O-R11, halogen, - (C- | -C4) -alkyl-O-R11 or phenyl,
R7 für Wasserstoffatom oder -(C<|-C4)-Alkyl steht, R9 für Wasserstoffatom oder -(C -| -C4J-AI ky I steht,R7 is hydrogen atom or - (C <| -C4) alkyl, R9 is hydrogen atom or - (C - | 4 J-AI is -C ky I,
R11 und R12 gleich oder verschieden sind und unabhängig voneinander für 1) Wasserstoffatom, 2) -(C-i-C^-Alkyl,R 11 and R 12 are identical or different and independently of one another represent 1) hydrogen, 2) - (C 1 -C 4) -alkyl,
3) -(Cn-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch Halogen, -OH oder -O-(C-|-C4)-Alkyl substituiert ist,3) - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or independently of one another mono-, di- or trisubstituted by halogen, -OH or -O- (C 1 -C 4) -alkyl,
4) -(Crj-C4)-Alkylen-(C3-C-|2)-Cycloalkyl, wobei Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch R13,4) - (Crj-C4) -alkylene- (C3-C-2) -cycloalkyl, where cycloalkyl is unsubstituted or independently of one another once, twice, three or four times by R13,
Halogen, -C(O)-O-RI 3, -(C-|-C4)-Alkyl-O-R13, -O-(Ci-C4)-Alkyl oderHalogen, -C (O) -O-RI 3, - (C-C 4 ) -alkyl-O-R 13, -O- (C 1 -C 4 ) -alkyl or
-(Crj-C4)-Alkylen-Phenyl substituiert ist,- (Cr j-C4) alkylene-phenyl,
5) -(Cn-C4)-Alkylen-C(O)-N(R13)2 oder5) - (Cn-C4) -alkylene-C (O) -N (R13) 2, or
6) -(Crj-C4)-Alkylen-Indolyl, stehen, R13 für 1) Wasserstoffatom,6) - (C 1 -C 4) -alkylene-indolyl, R 13 is 1) hydrogen,
2) -(C1-C4)-Alkyl,2) - (C 1 -C 4 ) -alkyl,
3) -(Cn-C4)-Alkylen-C(O)-O-R14,3) - (Cn-C4) -alkylene-C (O) -O-R14,
4) -(Co-C4)-Alkylen-C(O)-R14 oder4) - (Co-C 4) -alkylene-C (O) -R 14 or
5) -(Crj-C4)-Alkylen-O-R14 steht, 1725) - (Crj-C4) -alkylene-O-R14, 172
R14 für Wasserstoffatom, -(C<|-C4)-Alkyl, -NH2 oder -OH, steht und R15 für Wasserstoffatom, -(C-i-C^-Alkyl, -0-CF3, -NH2, -OH, -CF3 oder Halogen steht.R14 is hydrogen atom, - (C <| -C4) alkyl, -NH 2 or -OH, and R15 stands for hydrogen atom, - ^ (CiC alkyl, -0-CF 3, -NH 2, -OH, -CF 3 or halogen is.
18. Verbindung der Formel I gemäß Anspruch 16 oder 17, wobei R1 für 1) Wasserstoffatom oder 2) -(C-|-C-4)-Alkyl, steht,18. A compound of the formula I as claimed in claim 16 or 17, where R 1 is hydrogen or 2) - (C 1 -C 4) -alkyl,
R2 für 1) -(C1-C6)-Alkylen-NH2,R 2 for 1) - (C 1 -C 6 ) -alkylene-NH 2,
2) -(C1-C4)-Alkylen-Pyridyl-NH2, 3) -(C1-C4)-Alkylen-Piperidinyl-NH2,2) - (C 1 -C 4) -alkylene-pyridyl-NH 2, 3) - (C 1 -C 4) -alkylene-piperidinyl-NH 2,
4) -(C1-C6)-Alkylen-NH-C(=NH)-NH2,4) - (C 1 -C 6) -alkylene-NH-C (= NH) -NH 2 ,
5) -(C0-C4)-Alkylen-(C3-C6)-Cycloalkyl-NH2,5) - (C 0 -C 4 ) -alkylene- (C 3 -C 6 ) -cycloalkyl-NH 2,
6) -(C1-C6)-Alkylen-NH-C(=NH)-(Ci-C4)-Alkyl,6) - (C 1 -C 6 ) -alkylene-NH-C (= NH) - (C 1 -C 4 ) -alkyl,
7) -(C1-C4)-Alkylen-O-NH-C(=NH)-NH2i 8) -(C1 -C6)-Alkylen-NH-C(O)-O-(Ci-C4)-Alkylen-Phenyl, wobei7) - (C 1 -C 4) -alkylene-O-NH-C (= NH) -NH 2 i 8) - (C 1 -C 6 ) -alkylene-NH-C (O) -O- (Ci-C 4 ) -alkylene-phenyl, wherein
Phenyl unsubstituiert oder durch -NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch R15 substituiert ist,Phenyl is unsubstituted or substituted by -NH 2 or substituted by -NH 2 and one, two or three times by R 15,
9) -(C1 -C4)-Alkylen-N H-C(O)-(C 1-C6)-Alkyl,9) - (C 1 -C 4 ) -alkylene-N HC (O) - (C 1 -C 6 ) -alkyl,
10) -(C1-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch - NH2 substituiert ist oder durch -NH2 und ein-, zwei- oder dreifach durch10) - (C 1 -C 4) -alkylene-phenyl, wherein phenyl is unsubstituted or substituted by - NH 2 or by -NH 2 and one, two or three times by
R15 substituiert ist,R 15 is substituted,
11) -(C1-C4)-Alkylen-SO2-(C1-C4)-Alkylen-NH2, oder11) - (C 1 -C 4) -alkylene-SO2- (C1-C4) alkylene-NH2, or
12) -(C1-C4)-Alkylen-S-(C1-C4)-Alkylen-NH2, steht, R3 für 1) -(Ci-C4)-Alkyl, 2) -(C1-C4)-Alkylen-(C3-C6)-Cycloalkyl,12) - (C 1 -C 4 ) -alkylene-S- (C 1 -C 4 ) -alkylene-NH 2, R 3 is 1) - (C 1 -C 4 ) -alkyl, 2) - (C 1 -C 4 ) alkylene- (C3-C6) -cycloalkyl,
3) -(C-|-C4)-Alkylen-Phenyl, wobei Phenyl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist, 1733) - (C 1 -C 4) -alkylene-phenyl, where phenyl is independently of one another monosubstituted, disubstituted or trisubstituted by R 15, 173
4) -(Ci-C6)-Alkylen-NH-C(O)-O-(C-i-C4)-Alkylen-Phenyl, wobei4) - (C 1 -C 6) -alkylene-NH-C (O) -O- (C 1 -C 4) -alkylene-phenyl, wherein
Phenyl unabhängig voneinander ein-, zwei- oder dreifach durch R15 substituiert ist,Phenyl is independently substituted once, twice or three times by R 15,
5) Wasserstoffatom steht, R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander für5) is hydrogen, R4 is -N (R6) 2, where R6 are the same or different and independently of one another
1) Wasserstoffatom,1) hydrogen atom,
2) -(C-i-C^-Alkyl,2) - (C 1 -C 4) -alkyl,
3) -(Co-C4)-Alkylen-(C3-C-|2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adaman- tanyl, 1 ,7,7-Trimethyl-bicyclo[3.1.1]heptanyl, Decahydro-naphthalenyl, Tetra- hydronaphthalenyl, Octahydro-4,7-methano-indenyl oder Bicyclo[2.2.1]-heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach substituiert ist durch -(C-|-C4)-Alkyl, -C(O)-O-RH oder -(C-|-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch Halogen substituiert ist,3) - (Co-C4) -alkylene- (C3-C- | 2) -cycloalkyl, where cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, 1, 7,7-trimethyl-bicyclo [3.1.1] heptanyl, decahydro-naphthalenyl, tetrahydronaphthalenyl, octahydro-4,7-methanoindenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently of one another, mono-, di-, tri- or tetravalent is substituted by - (C 1 -C 4) -alkyl, -C (O) -O-RH or - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or substituted by halogen,
4) -(Co-C4)-Alkylen-C(R11)(R12)-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adamantanyl, 1 ,7,7-Trimethyl-bicyclo[3.1.1]heptanyl, Decahydro- naphthalenyl, Tetrahydronaphthalenyl, Octahydro-4,7-methano-indenyl oder4) - (Co-C4) -alkylene-C (R11) (R12) - (C3-C12) -cycloalkyl, where cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, 1, 7,7- Trimethyl-bicyclo [3.1.1] heptanyl, decahydro-naphthalenyl, tetrahydronaphthalenyl, octahydro-4,7-methano-indenyl or
Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach substituiert ist durch -(Ci-C4)-Alkyl,Bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently of one another mono-, di-, tri- or tetra-substituted by - (C 1 -C 4) -alkyl,
-C(O)-O-RH oder -(C-I -C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch Halogen substituiert ist, 5) -(Crj-C4)-Alkylen-Het, wobei Het ausgewählt ist aus der Gruppe Acridinyl,-C (O) -O-RH or - (CI-C4) -alkylene-phenyl, wherein phenyl is unsubstituted or substituted by halogen, 5) - (Crj-C4) -alkylene-Het, wherein Het is selected from the group acridinyl,
Azepinyl, Azetidinyl, Aziridinyl, Benzimidazalinyl, Benzimidazolyl, Benzo[1 ,3]dioxolyl, Benzofuranyl, Benzothiofuranyl, Benzothiophenyl, Benzoxazolyl, Benzthiazolyl, Benztriazolyl, Benztetrazolyl, Benzisoxazolyl, Benzisothiazolyl, Carbazolyl, 4aH-Carbazolyl, Carbolinyl, Chinazolinyl, Chinolinyl, 4H-Chinolizinyl, Chinoxalinyl, Chinuclidinyl, Chromanyl, Chromenyl,Azepinyl, azetidinyl, aziridinyl, benzimidazalinyl, benzimidazolyl, benzo [1,3] dioxolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H- Quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl,
Cinnolinyl, Deca-hydrochinolinyl, Dibenzofuranyl, Dibenzothio-phenyl, 174Cinnolinyl, deca-hydroquinolinyl, dibenzofuranyl, dibenzothio-phenyl, 174
Dihydrofuran[2,3-b]-tetrahydrofuranyl, Dihydrofuranyl, Dioxolyl, Dioxanyl, 2H, 6H-1 ,5,2-Dithiazinyl, Furanyl, Furazanyl, Imidazolidinyl, Imidazolinyl, Imidazolyl, 1H-lndazolyl, Indolinyl, Indolizinyl, Indolyl, 3H-lndolyl, Isobenzofuranyl, Isochromanyl, Isoindazolyl, Isoindolinyl, Isoindolyl, Isochinolinyl (Benzimidazolyl), Isothiazolidinyl, 2-lsothiazolinyl, Isothiazolyl, Isoxazolyl,Dihydrofuran [2,3-b] tetrahydrofuranyl, dihydrofuranyl, dioxolyl, dioxanyl, 2H, 6H-1, 5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolidinyl, 2-isothiazolinyl, isothiazolyl, isoxazolyl,
Isoxazolidinyl, 2-lsoxazolinyl, Morpholinyl, Naphthyridinyl, Octahydroisochinolinyl, Oxadiazolyl, 1 ,2,3-Oxadiazolyl, 1 ,2,4-Oxadiazolyl, 1 ,2,5- Oxadiazolyl, 1 ,3,4-Oxadiazolyl, Oxazolidinyl, Oxazolyl, Oxazolidinyl, Oxothiolanyl, Pyrimidinyl, Phenanthridinyl, Phenanthrolinyl, Phenazinyl, Phenothiazinyl, Phenoxathiinyl, Phenoxazinyl, Phthalazinyl, Piperazinyl,Isoxazolidinyl, 2-isoxazolinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1, 2,3-oxadiazolyl, 1, 2,4-oxadiazolyl, 1, 2,5-oxadiazolyl, 1, 3,4-oxadiazolyl, oxazolidinyl, oxazolyl, Oxazolidinyl, oxothiolanyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,
Piperidinyl, Pteridinyl, Purynyl, Pyranyl, Pyrazinyl, Pyroazolidinyl, Pyrazolinyl, Pyrazolyl, Pyridazinyl, Pryidooxazolyl, Pyridoimidazolyl, Pyridothiazolyl, Pyridothiophenyl, Pyridinyl, Pyridyl, Pyrimidinyl, Pyrrolidinyl, Pyrrolinyl, 2H- Pyrrolyl, Pyrrolyl, Tetrahydrofuranyl, Tetrahydroisochinolinyl, Tetrahydrochinolinyl, Tetrahydropyridinyl, 6H-1 ,2,5-Thiadazinyl, 1 ,2,3-Piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl, 6H-1, 2,5-thiadazinyl, 1, 2,3-
Thiadiazolyl, 1 ,2,4-Thiadiazolyl, 1 ,2,5-Thiadiazolyl, 1 ,3,4-Thiadiazolyl, Thianthrenyl, Thiazolyl, Thienyl, Thienoimidazolyl, Thienooxazolyl, Thienopyridin, Thienothiazolyl, Thiomorpholinyl, Thiophenyl, Triazinyl, 1 ,2,3- Triazolyl, 1 ,2,3-Triazolyl, 1 ,2,4-Triazolyl, 1 ,2,5-Triazolyl, 1,3,4-Triazolyl und Xanthenyl, wobei Het oder Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch -(C-|-C4)-Alkyl substituiert istThiadiazolyl, 1, 2,4-thiadiazolyl, 1, 2,5-thiadiazolyl, 1, 3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienoimidazolyl, thienooxazolyl, thienopyridine, thienothiazolyl, thiomorpholinyl, thiophenyl, triazinyl, 1, 2, 3-triazolyl, 1, 2,3-triazolyl, 1, 2,4-triazolyl, 1, 2,5-triazolyl, 1,3,4-triazolyl and xanthenyl, wherein Het or alkylene is unsubstituted or independently of one another once or twice is substituted by - (C 1 -C 4) -alkyl
6) -(C-|-C6)-Alkylen-Phenyl, wobei Phenyl oder Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Halogen, Phenyl, -C(O)-O-RH , -(Ci-C4)-Alkyl-O-R11 , -O-(C-|-C4)-Alkyl oder -(C-i-C4)-Alkyl substituiert sind,6) - (C 1 -C 6) -alkylene-phenyl, where phenyl or alkylene is unsubstituted or independently of one another by one or two halogen, phenyl, -C (O) -O-RH, - (C 1 -C 4) -alkyl -O-R11, -O- (C- | -C4) alkyl or - (CiC 4) alkyl substituted,
7) -(Co-C4)-Alkylen-C(R11 )(R12)-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch Phenyl oder Fluor substituiert ist,7) - (Co-C4) -alkylene-C (R11) (R12) -phenyl, where phenyl is unsubstituted or independently of one another mono-, di- or trisubstituted by phenyl or fluorine,
8) 1 ,2,3,4-Tetrahydro-naphthalenyl, 9) -(C0-C4)-Alkylen-CH(R11)-C(O)-NH2,8) 1, 2,3,4-tetrahydro-naphthalenyl, 9) - (C 0 -C 4 ) -alkylene-CH (R 11) -C (O) -NH 2 ,
10) -(Co-C4)-Alkylen-CH(R11)-C(O)-NH-(Ci-C4)-Alkyl, 17510) - (Co-C4) -alkylene-CH (R11) -C (O) -NH- (C 1 -C 4 ) -alkyl, 175
11 ) -(Co-C4)-Alkylen-CH(R11 )-C(O)-NH-CH(R12)-R13,11) - (Co-C 4 ) -alkylene-CH (R 11) -C (O) -NH-CH (R 12) -R 13,
12) -(C-|-C6)-Alkylen-C(O)-O-R11 , wobei Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Halogen, Phenyl, -C(O)-O-RH , -(Ci-C4)-Alkyl-O-R11 , -O-CC-i-C^-Alkyl oder -fC-i-C^-Alkyl substituiert ist,12) - (C-C6) -alkylene-C (O) -O-R11, wherein alkyls are unsubstituted or independently of one another by one or two halo by halogen, phenyl, -C (O) -O-RH, - (Ci C4) -alkyl-O-R11, -O-CC-iC ^ -alkyl or -fC-iC ^ -alkyl substituted,
13) -(C0-C4)-Alkylen-C(R11 )(R12)-C(O)-O-R11 , oder13) - (C 0 -C 4 ) -alkylene-C (R 11) (R 12) -C (O) -O-R 11, or
14) -(C<|-C3)-Fluoralkyl, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom an das sie gebunden sind einen Mono- oder Bicyclischen Ring bilden ausgewählt aus der Gruppe Pyrrolidin, Piperidin, 2-Aza-bicyclo[3.2.2]nonan und 7-Aza-bicyclo[2.2.1]hep-tan, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(C<|-C4)-Alkyl, -14) - (C <| - C3) -Fluoralkyl, or the two radicals R6 together with the N-atom to which they are attached form a mono- or bicyclic ring selected from the group consisting of pyrrolidine, piperidine, 2-aza- bicyclo [3.2.2] nonane and 7-azabicyclo [2.2.1] hep-tane, the ring being unsubstituted or mono- or disubstituted by - (C 1 -C 4) -alkyl,
C(O)-O-R11 , -(C1-C4)-Alkyl-O-R11 oder Phenyl substituiert ist, R7 für Wasserstoffatom oder -(C-i-C-4)-Alkyl steht, R9 für Wasserstoffatom oder -(C-)-C4)-Alkyl steht, R11 und R12 gleich oder verschieden sind und unabhängig voneinander fürC (O) -O-R11, - (C 1 -C 4) -alkyl-O-R 11 or phenyl, R 7 is hydrogen or - (C 1 -C 4) -alkyl, R 9 is hydrogen or - (C-) C4) alkyl, R11 and R12 are the same or different and are each independently
1) Wasserstoffatom,1) hydrogen atom,
2) -(C-i-C^-Alkyl,2) - (C 1 -C 4) -alkyl,
3) -(Crj-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch -OH, Halogen oder -O-(Ci -C^)-Al kyl substituiert ist,3) - (Cr j-C4) alkylene-phenyl, where phenyl is unsubstituted or independently mono-, di- or trisubstituted by OH, halogen or -O- (Ci -C ^) - Al is alkyl substituted,
4) -(Crj-C4)-Alkylen-(C3-C-|2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adamantanyl, Bicyclo[3.1.1 ]heptanyl, Decahydro-naphthalenyl, Octahydro-4,7-methano- indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch -(C-|-C4)-Alkyl, -4) - (Crj-C4) -alkylene- (C3-C- | 2) -cycloalkyl, wherein cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, bicyclo [3.1.1] heptanyl, decahydro-naphthalenyl , Octahydro-4,7-methanoindenyl or bicyclo [2.2.1] heptanyl and in which cycloalkyl is unsubstituted or independently of one another mono-, di-, tri- or tetra-substituted by - (C 1 -C 4) -alkyl,
C(O)-O-RI 3 oder Phenyl substituiert ist, oderC (O) -O-RI 3 or phenyl, or
5) -(Cfj-C4)-Alkylen-Indolyl, stehen,5) - (Cf j -C4) -alkylene-indolyl,
R13 für 1 ) Wasserstoffatom, 2) -(C^C^-Alkyl, 3) -(C0-C4)-Alkylen-C(O)-O-R14, 176R13 represents 1) hydrogen, 2) - (C 1 -C 4 -alkyl, 3) - (C 0 -C 4 ) -alkylene-C (O) -O-R 14, 176
4) -(C0-C4)-Alkylen-C(O)-R14 oder4) - (C 0 -C 4 ) -alkylene-C (O) -R 14 or
5) -(Co-C4)-Alkylen-O-R14 steht, und5) - (Co-C4) -alkylene-O-R14, and
R14 für Wasserstoff atom, -(C-|-C4)-Alkyl, -NH2 oder -OH steht und R15 für Wasserstoffatom, -(Ci-C4)-Alkyl, -0-CF3, -NH2, -OH, -CF3 oder Halogen steht.R14 is hydrogen atom, - (C- | -C4) -alkyl, -NH 2 or -OH, and R15 are hydrogen atom, - (Ci-C4) alkyl, -0-CF 3, -NH 2, -OH , -CF 3 or halogen.
19. Verbindung der Formel I gemäß der Ansprüche 16 bis 18, wobei R1 für 1) Wasserstoffatom oder 2) -(C1-C4)-Alkyl, steht, R2 für 1) -(C1-C6)-Alkylen-NH2,19. A compound of the formula I as claimed in claims 16 to 18, where R 1 is hydrogen or 2) - (C 1 -C 4 ) -alkyl, R 2 is 1) - (C 1 -C 6 ) -alkylene NH 2 ,
2) -(C1-C4)-Alkylen-Pyridyl-NH2,2) - (C 1 -C 4 ) -alkylene-pyridyl-NH 2,
3) -(C-|-C4)-Alkylen-Piperidinyl-NH2,3) - (C 1 -C 4 ) -alkylene-piperidinyl-NH 2,
4) -(C1-C4)-Alkylen-NH-C(=NH)-NH2,4) - (C 1 -C 4) alkylene-NH-C (= NH) -NH 2,
5) -(C <\ -C6)-Alkylen-NH-C(=NH)-(C 1 -C4)-Alkyl, 6) -(Ci-C4)-Alkylen-(C3-C6)-Cycloalkyl-NH2,5) - (C <\ -C6) alkylene-NH-C (= NH) - (C 1 -C 4) -alkyl, 6) - (Ci-C4) alkylene- (C3-C6) - Cycloalkyl-NH 2 ,
7) -(C1-C4)-Alkylen-O-NH-C(=NH)-NH2i 7) - (C 1 -C 4 ) alkylene-O-NH-C (= NH) -NH 2i
8) -(C -i -C6)-Alkylen-N H-C(O)-O-(C 1 -C4)-Alkylen-Phenyl ,8) - (C 1 -C 6 ) -alkylene-N HC (O) -O- (C 1 -C 4 ) -alkylene-phenyl,
9) -(C-|-C4)-Alkylen-NH-C(O)-(Ci-C6)-Alkyl oder9) - (C 1 -C 4 ) -alkylene-NH-C (O) - (C 1 -C 6 ) -alkyl or
10) -(C-i-C4)-Alky!en-Phenyl-NH2, 11) -(C1-C2)-Alkylen-SO2-(C1-C4)-Alkylen-NH2, oder10) - (CiC 4) -Alky en-phenyl-NH 2, 11) - (C 1 -C 2) -alkylene-SO2- (C 1 -C 4) alkylene-NH 2, or
12) -(C1-C2)-Alkylen-S-(C1-C4)-Alkylen-NH2, steht,12) - (C 1 -C 2 ) -alkylene-S- (C 1 -C 4 ) -alkylene-NH 2,
R3 für 1) -(C-|-C4)-Alkyl,R 3 is 1) - (C 1 -C 4 ) -alkyl,
2) -(C-i-C4)-Alkylen-(C3-C6)-Cycloalkyl,2) - (C 1 -C 4 ) -alkylene- (C 3 -C 6) -cycloalkyl,
3) -(C-|-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder durch - OH substituiert ist,3) - (C 1 -C 4 ) -alkylene-phenyl, where phenyl is unsubstituted or substituted by -OH,
A) -(Ci-C6)-Alkylen-NH-C(O)-O-(Ci-C4)-Alkylen-Phenyl,A) - (C 1 -C 6 ) -alkylene-NH-C (O) -O- (C 1 -C 4 ) -alkylene-phenyl,
5) Wasserstoffatom steht, R4 für -N(R6)2, steht, wobei R6 gleich oder verschieden sind und unabhängig voneinander für 1775) is hydrogen, R4 is -N (R6) 2, where R6 are the same or different and independently of one another 177
1) Wasserstoffatom,1) hydrogen atom,
2) -(C1-Ce)-AIKyI,2) - (C 1 -Ce) -Alkyl,
3) -(Co-C4)-Alkylen-(C3-C8)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclopropyl, Adamantanyl, 1 ,7,7- Trimethyl-bicyclo[3.1.1]heptanyl, Decahydro-naphthalenyl, Octahydro-4,7- methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch -(C-|-C4)-Alkyl oder Phenyl substituiert ist,3) - (C 1 -C 4) -alkylene- (C 3 -C 8) -cycloalkyl, where cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclopropyl, adamantanyl, 1, 7,7-trimethyl-bicyclo [3.1.1] heptanyl, Decahydro-naphthalenyl, octahydro-4,7-methano-indenyl or bicyclo [2.2.1] heptanyl and wherein cycloalkyl is unsubstituted or independently mono-, di- or trisubstituted by - (C 1 -C 4) -alkyl or phenyl .
4) -C(R11)(R12)-Adamantanyl, 5) -CH(R11)-C(O)-NH-CH(R12)-R13,4) -C (R11) (R12) -adamantanyl, 5) -CH (R11) -C (O) -NH-CH (R12) -R13,
6) -(Crj-C4)-Alkylen-Het, wobei Het ausgewählt ist aus der Gruppe6) - (Crj-C4) -alkylene-Het, wherein Het is selected from the group
Benzimidazolyl, Isoxazolyl, Piperidinyl, Pyridyl, Pyrrolidinyl, Thiophenyl und Benzo[1 ,3]dioxolyl,Benzimidazolyl, isoxazolyl, piperidinyl, pyridyl, pyrrolidinyl, thiophenyl and benzo [1,3] dioxolyl,
7) 1 ,2,3,4-Tetrahydro-naphthalenyl, 8) -(Co-C4)-Alkylen-C(R11 )(R12)-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch Phenyl oder Fluor substituiert ist,7) 1, 2,3,4-tetrahydro-naphthalenyl, 8) - (Co-C4) -alkylene-C (R11) (R12) -phenyl, wherein phenyl unsubstituted or independently of one another, mono-, di- or trisubstituted by phenyl or fluorine is substituted,
9) -CH(RH)-C(O)-NH2,9) -CH (RH) -C (O) -NH 2 ,
10) -CH(RI 1)-C(O)-NH-CH(R12)-CH2-OH, 11) -(C-|-Cö)-Alkylen-Phenyl, wobei Phenyl oder Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Chlor, Fluor, -C(O)-O-RH , -(C1-C4)-Alkyl-O-R11, -O-(C-|-C4)-Alkyl, Phenyl oder10) -CH (RI 1) -C (O) -NH-CH (R 12) -CH 2 -OH, 11) - (C 1 -C 6) -alkylene-phenyl, where phenyl or alkylene are unsubstituted or independently of one another or two times by chlorine, fluorine, -C (O) -O-RH, - (C 1 -C 4) -alkyl-O-R 11, -O- (C-C 4) -alkyl, phenyl or
-(Ci-C4)-Alkyl substituiert sind, 12) -CH(RI I)-C(O)-NH-(C1 -C4)-Alkyl, 13) -(C0-C4)-Alkylen-C(R11)(R12)-Bicyclo[3.1.1]heptanyl, wobei(C 1 -C 4 ) -alkyl, 12) -CH (RI 1) -C (O) -NH- (C 1 -C 4 ) -alkyl, 13) - (C 0 -C 4 ) -alkylene C (R11) (R12) bicyclo [3.1.1] heptanyl, wherein
Bicyclo[3.1.1]heptanyl unsubstituiert oder ein- bis vierfach durch -(C-|-C4)-Alkyl substituiert ist,Bicyclo [3.1.1] heptanyl is unsubstituted or substituted one to four times by - (C 1 -C 4) -alkyl,
14) -(C1-C6)-Alkylen-C(O)-O-R11 , wobei Alkylen unsubstituiert oder unabhängig voneinander ein- oder zweifach durch Chlor, Fluor, -C(O)-O-RH , - 17814) - (C 1 -C 6) -alkylene-C (O) -O-R 11, where alkylene is unsubstituted or independently of one another by chlorine, fluorine, -C (O) -O-RH, - 178
(Ci-C4)-Alkyl-0-R11 , -O-(C<|-C4)-Alkyl, Phenyl oder -(C-|-C4)-Alkyl substituiert ist,(C 1 -C 4 ) -alkyl-0-R 11, -O- (C 1 -C 4 ) -alkyl, phenyl or - (C 1 -C 4 ) -alkyl,
15) -(Co-C4)-Alkylen-C(R11 )(R12)-C(O)-O-R11 , oder15) - (Co-C 4) -alkylene-C (R11) (R12) -C (O) -O-R11, or
16) -CH2-CF2-CF3, stehen, oder die beiden Reste R6 zusammen mit dem N-Atom an das sie gebunden sind einen Mono- oder Bicyclischen Ring bilden, ausgewählt aus der Gruppe Pyrrolidine, 2-aza-bicyclo[3.2.2]nonan und 7-aza-bicyclo[2.2.1]heptan, wobei der Ring unsubstituiert oder ein- oder zweifach durch -(Ci-C4)-Alkyl,16) -CH2-CF2-CF3, or the two radicals R6 together with the N-atom to which they are attached form a mono- or bicyclic ring selected from the group consisting of pyrrolidines, 2-aza-bicyclo [3.2.2 ] nonane and 7-aza-bicyclo [2.2.1] heptane, where the ring is unsubstituted or mono- or disubstituted by - (C 1 -C 4) -alkyl,
-C(O)-O-RH , -(C-|-C4)-Alkyl-O-R11 oder Phenyl substituiert ist, R7 für Wasserstoffatom oder -(C 1 -C4)-Alkyl steht,-C (O) -O-RH, - (C-C4) -alkyl-O-R11 or phenyl, R7 is hydrogen or - (C 1 -C 4) -alkyl,
R9 für Wasserstoffatom oder -(C-|-C4)-Alkyl steht,R 9 is hydrogen or - (C 1 -C 4) -alkyl,
R11 und R12 gleich oder verschieden sind und unabhängig voneinander fürR11 and R12 are the same or different and independently of each other
1) Wasserstoff atom,1) hydrogen atom,
2) -(C-i-C^-Alkyl, 3) -(Crj-C4)-Alkylen-Phenyl, wobei Phenyl unsubstituiert oder unabhängig voneinander ein-, zwei- oder dreifach durch -OH, Halogen oder -O-(Ci-C4)-Alkyl substituiert ist,2) - (C 1 -C 4 -alkyl, 3) - (C 1 -C 4) -alkylene-phenyl, where phenyl is unsubstituted or independently mono-, di- or trisubstituted by -OH, halogen or -O- (C 1 -C 4) - Alkyl is substituted,
4) -(Crj-C4)-Alkylen-(C3-Ci2)-Cycloalkyl, wobei Cycloalkyl ausgewählt ist aus der Gruppe Cyclohexyl, Cyclopentyl, Cyclobutyl, Cyclopropyl, Adaman- tanyl, 1 ,7,7-Trimethyl-bicyclo[3.1.1 ]heptanyl, Decahydro-naphthalenyl,4) - (Crj-C4) -alkylene- (C3-Ci2) -cycloalkyl, wherein cycloalkyl is selected from the group cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, adamantanyl, 1, 7,7-trimethyl-bicyclo [3.1. 1] heptanyl, decahydro-naphthalenyl,
Octahydro-4,7-methano-indenyl oder Bicyclo[2.2.1]heptanyl und worin Cycloalkyl unsubstituiert oder unabhängig voneinander ein-, zwei-, drei- oder vierfach durch -(C-|-C4)-Alkyl, -C(O)-O-RI 3 oder Phenyl substituiert ist, oderOctahydro-4,7-methanoindenyl or bicyclo [2.2.1] heptanyl and wherein cycloalkyl is unsubstituted or independently mono-, di-, tri or tetra- by - (C 1 -C 4) -alkyl, -C (O ) -O-RI 3 or phenyl, or
5) -(Cn-C4)-Alkylen-Indolyl, stehen, R13 für 1) Wasserstoff atom,5) - (Cn-C4) -alkylene-indolyl, R13 is 1) hydrogen atom,
2) -(C-i-C^-Alkyl,2) - (C 1 -C 4) -alkyl,
3) -(Cfj-C4)-Alkylen-C(O)-O-R14,3) - (j Cf-C4) -alkylene-C (O) -O-R14,
4) -(Co-C4)-Alkylen-C(O)-R14 oder4) - (Co-C4) -alkylene-C (O) -R14 or
5) -(Crj-C4)-Alkylen-O-R14 steht, R14 für Wasserstoffatom, -(C-|-C4)-Alkyl, -NH2 oder -OH steht und 1795) - (j Cr C4) -alkylene-O-R14, R14 is hydrogen atom, - (C- | -C4) alkyl, -NH2 or -OH and 179
R15 für Wasserstoffatom, -(C<|-C4)-Alkyl, -O-CF3, -NH2, -OH, -CF3 oder Halogen steht.R 15 is hydrogen, - (C 1 -C 4) -alkyl, -O-CF 3, -NH 2, -OH, -CF 3 or halogen.
20. Verbindung der Formel I gemäß einem oder mehreren der Ansprüche 16 bis 19, dadurch gekennzeichnet, dass es die Verbindung der Formel I20. A compound of formula I according to one or more of claims 16 to 19, characterized in that it is the compound of formula I
(S)-6-Amino-2-{3-[(R)-1-(3-methyl-butylcarbamoyl)-2-phenyl-ethyl]-ureido}- hexansäure Hydrochlorid, (S)-6-Amino-2-{3-[(R)-5-benzyloxycarbonylamino-1 - (3-methyl-butylcarbamoyl)-pentyl]-ureido}-hexansäure, (S)-6-Amino-2-{3-[(R)-1- (3-methyl-butylcarbamoyl)-ethyl]-ureido}-hexansäure, (S)-6-Amino-2-{3-[(R)-3- methyl-1-(3-methyl-butylcarbamoyl)-butyl]-ureido}-hexansäure, (S)-6-Amino-2-(S) -6-Amino-2- {3 - [(R) -1- (3-methyl-butylcarbamoyl) -2-phenyl-ethyl] -ureido} -hexanoic acid hydrochloride, (S) -6-amino-2 - {3 - [(R) -5-benzyloxycarbonylamino-1 - (3-methyl-butylcarbamoyl) -pentyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3 - [(R) -1 - (3-methyl-butylcarbamoyl) -ethyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3 - [(R) -3-methyl-1- (3-methylbutylcarbamoyl) -butyl ] -ureido} -hexanoic acid, (S) -6-amino-2-
{3-[(R)-1-(3-methyl-butylcarbamoyl)-butyl]-ureido}-hexansäure, (S)-6-Amino-2- {3-[(R)-1-(3-methyl-butylcarbamoyl)-pentyl]-ureido}-hexansäure, (S)-6-Amino-2- {3-[(R)-1-(3-methyl-butylcarbamoyl)-2-phenyl-ethyl]-ureido}-hexansäure, (S)-6- Amino-2-[3-((R)-1-isobutylcarbamoyl-2-phenyl-ethyl)-ureido]-hexansäure, (S)-6- Amino-2-{3-[(R)-5-benzyloxy-carbonylamino-1 -((S)-1 -ethylcarbamoyl-2-methyl- propylcarbamoyl)-pentyl]-ureido}-hexansäure, (S)-6-Amino-2-{3-[(R)-2- cyclohexyl-1-((S)-1-ethylcarb-amoyl-2-methyl-propylcarb-amoyl)-ethyl]-ureido}- hexansäure, (S)-6-Amino-2-{3-[(R)-2-cyclohexyl-1-(2,4-difluoro- benzylcarbamoyl)-ethyl]-ureido}-hexansäure, (S)-6-Amino-2-{3-[(R)-2- cyclohexyl-1 -(2-phenyl-propylcarb-amoyl)-ethyl]-ureido}-hexansäure, (S)-6-{3 - [(R) -1- (3-methyl-butylcarbamoyl) -butyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3 - [(R) -1- (3-methyl -butylcarbamoyl) -pentyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3 - [(R) -1- (3-methyl-butylcarbamoyl) -2-phenyl-ethyl] -ureido} - hexanoic acid, (S) -6-amino-2- [3 - ((R) -1-isobutylcarbamoyl-2-phenyl-ethyl) -ureido] -hexanoic acid, (S) -6-amino-2- {3- [ (R) -5-benzyloxy-carbonylamino-1 - ((S) -1-ethylcarbamoyl-2-methyl-propylcarbamoyl) -pentyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3- [ (R) -2-cyclohexyl-1 - ((S) -1-ethylcarbamoyl-2-methyl-propylcarbamoyl) -ethyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3 - [(R) -2-cyclohexyl-1- (2,4-difluoro-benzylcarbamoyl) -ethyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3 - [(R) -2- cyclohexyl-1 - (2-phenyl-propylcarbamoyl) -ethyl] -ureido} -hexanoic acid, (S) -6-
Amino-2-{3-[(R)-2-cyclohexyl-1-(2-o-tolyl-ethylcarbamoyl)-ethyl]-ureido}- hexansäure, (S)-6-Amino-2-{3-[(R)-1-(4-chloro-benzylcarbamoyl)-2-cyclohexyl- ethyl]-ureido}-hexansäure, (S)-6-Amino-2-{3-[(R)-2-cyclohexyl-1-((R)-1-phenyl- ethylcarbamoyl)-ethyl]-ureido}-hexansäure, (S)-6-Amino-2-{3-[(R)-1- (bicyclo[2.2.1]hept-2-ylcarbamoyl)-2-cyclohexyl-ethyl]-ureido}-hexansäure, (S)-Amino-2- {3 - [(R) -2-cyclohexyl-1- (2-o-tolyl-ethylcarbamoyl) -ethyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3- [ (R) -1- (4-chloro-benzylcarbamoyl) -2-cyclohexyl-ethyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3 - [(R) -2-cyclohexyl-1 ((R) -1-phenylethylcarbamoyl) ethyl] ureido} hexanoic acid, (S) -6-amino-2- {3 - [(R) -1- (bicyclo [2.2.1] hept-2 -ylcarbamoyl) -2-cyclohexyl-ethyl] -ureido} -hexanoic acid, (S) -
6-Amino-2-{3-[(R)-2-cyclohexyl-1-((R)-1-methoxycarbonyl-ethylcarbamoyl)- ethyl]-ureido}-hexansäure, (S)-6-Amino-2-{3-[(R)-2-cyclohexyl-1-(3-phenyl- propylcarbamoyl)-ethyl]-ureido}-hexansäure, (S)-6-Amino-2-{3-[(R)-2- cyclohexyl-1-(2-methyl-cyclohexylcarbamoyl)-ethyl]-ureido}-hexansäure, (S)-6- Amino-2-(3-{(R)-1 -[(S)-1 -(4-chloro-phenyl)-ethylcarbamoyl]-2-cyclohexyl-ethyl}- ureido)-hexansäure, (S)-6-Amino-2-{3-[(R)-2-cyclohexyl-1-(4-methoxy- benzylcarbamoyl)-ethyl]-ureido}-hexansäure, (S)-6-Amino-2-(3-{(R)-2- 1806-Amino-2- {3 - [(R) -2-cyclohexyl-1 - ((R) -1-methoxycarbonyl-ethylcarbamoyl) -ethyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3 - [(R) -2-cyclohexyl-1- (3-phenyl-propylcarbamoyl) -ethyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3 - [(R) -2- cyclohexyl-1- (2-methyl-cyclohexylcarbamoyl) -ethyl] -ureido} -hexanoic acid, (S) -6-amino-2- (3 - {(R) -1 - [(S) -1 - (4- chloro-phenyl) -ethylcarbamoyl] -2-cyclohexyl-ethyl} - ureido) -hexanoic acid, (S) -6-amino-2- {3 - [(R) -2-cyclohexyl-1- (4-methoxybenzylcarbamoyl ) -ethyl] -ureido} -hexanoic acid, (S) -6-amino-2- (3 - {(R) -2- 180
cyclohexyl-1-[(3-methyl-isoxazol-5-ylmethyl)-carbamoyl]-ethyl}-ureido)- hexansäure, (S)-6-Amino-2-{3-[(R)-2-cyclohexyl-1 -((R)-1 -phenyl- ethylcarbamoyl)-ethyl]-ureido}-hexansäure, (S)-6-Amino-2-{3-[2-(7-aza- bicyclo[2.2.1 ]hept-7-yl)-1 -cyclohexylmethyl-2-oxo-ethyl]-ureido}-hexansäure, (S)-6-Amino-2-{3-[(R)-5-benzyloxycarbonylamino-1 -(1 -methoxycarbonyl-1 - methyl-ethylcarbamoyl)-pentyl]-ureido}-hexansäure, (S)-6-Amino-2-{3-[(R)-2- cyclohexyl-1-(2,3-dimethyl-benzylcarbamoyl)-ethyl]-ureido}-hexansäure, (S)-6- Amino-2-{3-[(R)-2-cyclohexyl-1-(1 ,2-dimethyl-butylcarbamoyl)-ethyl]-ureido}- hexansäure, (S)-6-Amino-2-{3-[(R)-2-cyclohexyl-1-(2,2-diphenyl- ethylcarbamoyl)-ethyl]-ureido}-hexansäure, (S)-6-Amino-2-{3-[(R)-2-cyclohexyl-cyclohexyl-1 - [(3-methyl-isoxazol-5-ylmethyl) -carbamoyl] -ethyl} -ureido) -hexanoic acid, (S) -6-amino-2- {3 - [(R) -2-cyclohexyl- 1 - ((R) -1-phenyl-ethylcarbamoyl) -ethyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3- [2- (7-azabicyclo [2.2.1] hept -7-yl) -1-cyclohexylmethyl-2-oxo-ethyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3 - [(R) -5-benzyloxycarbonylamino-1 - (1-methoxycarbonyl -1-methyl-ethylcarbamoyl) -pentyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3 - [(R) -2-cyclohexyl-1- (2,3-dimethyl-benzylcarbamoyl) - ethyl] -urido} -hexanoic acid, (S) -6-amino-2- {3 - [(R) -2-cyclohexyl-1- (1,2-dimethyl-butyl-carbamoyl) -ethyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3 - [(R) -2-cyclohexyl-1- (2,2-diphenyl-ethylcarbamoyl) -ethyl] -ureido} -hexanoic acid, (S) -6-amino- 2- {3 - [(R) -2-cyclohexyl-
1-(2,2-dimethyl-propylcarbamoyl)-ethyl]-ureido}-hexansäure, (S)-6-Amino-2-{3- [(R)-1-(2-benzo[1 ,3]dioxol-5-yl-ethylcarb-amoyl)-2-cyclohexyl-ethyl]-ureido}- hexansäure, (S)-6-Amino-2-{3-[(R)-2-cyclohexyl-1 -(4-methyl- cyclohexylcarbamoyl)-ethyl]-ureido}-hexansäure, (S)-6-Amino-2-{3-[(R)-5- benzyloxycarbonylamino-1 -((S)-1 -ethoxycarbonyl-3-methyl-butylcarbamoyl)- pentyl]-ureido}-hexansäure, (1 R,2S)-2-{(R)-2-[3-((S)-5-Amino-1 -carboxy-pentyl)- ureidol-θ-benzyloxycarbonylamino-hexanoylaminoj-cyclohexane- carbonsäureethylester, (S)-6-Amino-2-{3-[(R)-5-benzyloxycarbonylamino-1-(2- phenyl-propylcarbamoyl)-pentyl]-ureido}-hexansäure, (S)-6-Amino-2-(3-{(R)-5- benzyloxycarbonylamino-1 -[(biphenyl-2-ylmethyl)-carbamoyl]-pentyl}-ureido)- hexansäure, (S)-6-Amino-2-{3-[(R)-5-benzyloxycarbonylamino-1-((R)-1- ethoxycarbonyl-2-phenyl-ethylcarbamoyl)-pentyl]-ureido}-hexansäure, (S)-6- Amino-2-{3-[(R)-5-benzyloxycarbonyl-amino-1-((1S,2S)-1-methoxycarbonyl-2- methyl-butylcarbamoyl)-pentyl]-ureido}-hexansäure, (S)-6-Amino-2-{3-[(R)-5- benzyloxycarbonylamino-1 -((S)-1-ethoxycarbonyl-2-methyl-propylcarbamoyl)- pentyl]-ureido}-hexansäure, 1 -{(R)-2-[3-((S)-5-Amino-1 -carboxy-pentyl)-ureido]- 6-benzyloxycarbonylamino-hexanoylamino}-cyclopentanecarboxylic acid methyl ester, (S)-2-(3-{(R)-1 -[(S)-1 -((S)- 1 -Benzyl-2-hydroxy-ethylcarbamoyl)-2-methyl- propylcarbamoyl]-2-cyclohexyl-ethyl}-ureido)-5-benzyloxycarbonylamino- pentansäure, (S)-6-Amino-2-{3-[(R)-2-cyclohexyl-1-(3-methyl- cyclohexylcarbamoyl)-ethyl]-ureido}-hexansäure, (S)-6-Amino-2-{3-[(R)-5- benzyloxycarbonylamino-1-(2-methyl-cyclohexylcarbamoyl)-pentyl]-ureido}- 1811- (2,2-dimethyl-propylcarbamoyl) -ethyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3- [(R) -1- (2-benzo [1,3] dioxole -5-yl-ethylcarbamoyl) -2-cyclohexyl-ethyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3 - [(R) -2-cyclohexyl-1 - (4-methyl - cyclohexylcarbamoyl) -ethyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3 - [(R) -5-benzyloxycarbonylamino-1 - ((S) -1-ethoxycarbonyl-3-methylbutylcarbamoyl ) - pentyl] -ureido} -hexanoic acid, (1R, 2S) -2 - {(R) -2- [3 - ((S) -5-amino-1-carboxypentyl) -uridol-θ-benzyloxycarbonylamino ethylhexanoylaminoj-cyclohexane-carboxylate, (S) -6-amino-2- {3 - [(R) -5-benzyloxycarbonylamino-1- (2-phenyl-propylcarbamoyl) -pentyl] -ureido} -hexanoic acid, (S) -6-amino-2- (3 - {(R) -5-benzyloxycarbonylamino-1 - [(biphenyl-2-ylmethyl) -carbamoyl] -pentyl} -ureido) -hexanoic acid, (S) -6-amino-2 - {3 - [(R) -5-benzyloxycarbonylamino-1 - ((R) -1-ethoxycarbonyl-2-phenyl-ethylcarbamoyl) -pentyl] -ureido} -hexanoic acid, (S) -6-amino-2- { 3 - [(R) -5-benzyloxycarbonyl-amino-1 - ((1S, 2S) -1-methoxycarbonyl-2-methylbutylcarbamoyl) -pentyl] -urea ido} -hexanoic acid, (S) -6-amino-2- {3 - [(R) -5-benzyloxycarbonylamino-1 - ((S) -1-ethoxycarbonyl-2-methyl-propylcarbamoyl) -pentyl] -ureido} hexanoic acid, 1 - {(R) -2- [3 - ((S) -5-amino-1-carboxypentyl) ureido] - 6-benzyloxycarbonylaminohexanoylamino} -cyclopentanecarboxylic acid methyl ester, (S) - 2- (3 - {(R) -1 - [(S) -1 - ((S) -1-Benzyl-2-hydroxy-ethylcarbamoyl) -2-methyl-propylcarbamoyl] -2-cyclohexyl-ethyl} -ureido ) -5-benzyloxycarbonylaminopentanoic acid, (S) -6-amino-2- {3 - [(R) -2-cyclohexyl-1- (3-methylcyclohexylcarbamoyl) -ethyl] -ureido} -hexanoic acid, (S. ) -6-amino-2- {3 - [(R) -5-benzyloxycarbonylamino-1- (2-methyl-cyclohexylcarbamoyl) -pentyl] -ureido} - 181
hexansäure, (S)-6-Amino-2-{3-[(R)-5-benzyloxycarbonylamino-1 -((1 S,4R)- bicyclo[2.2.1 ]hept-2-ylcarbamoyl)-pentyl]-ureido}-hexansäure, (S)-6-Amino-2-(3- {(R)-5-benzyloxycarbonyl-amino-1-[(S)-1-(4-chloro-phenyl)-ethylcarbamoyl]- pentyl}-ureido)-hexansäure, (S)-6-Amino-2-(3-{(R)-5-benzyloxycarbonylamino-1- [(3-methyl-isoxazol-5-ylmethyl)-carbamoyl]-pentyl}-ureido)-hexansäure, (S)-6-hexanoic acid, (S) -6-amino-2- {3 - [(R) -5-benzyloxycarbonylamino-1 - ((1S, 4R) -bicyclo [2.2.1] hept-2-ylcarbamoyl) -pentyl] - ureido} -hexanoic acid, (S) -6-amino-2- (3- {(R) -5-benzyloxycarbonyl-amino-1 - [(S) -1- (4-chlorophenyl) -ethylcarbamoyl] -pentyl } -ureido) -hexanoic acid, (S) -6-amino-2- (3 - {(R) -5-benzyloxycarbonylamino-1- [(3-methyl-isoxazol-5-ylmethyl) -carbamoyl] -pentyl} - ureido) -hexanoic acid, (S) -6-
Amino-2-{3-[(R)-5-benzyloxycarbonylamino-1-((R)-1-methoxycarbonyl- ethylcarbamoyl)-pentyl]-ureido}-hexansäure, (S)-6-Amino-2-{3-[(R)-5- benzyloxycarbonylamino-1-((R)-1-phenyl-ethylcarbamoyl)-pentyl]-ureido}- hexansäure, (S)-6-Amino-2-{3-[(R)-5-benzyloxycarbonylamino-1-(3-phenyl- propylcarbamoyl)-pentyl]-ureido}-hexansäure, (S)-6-Amino-2-{3-[(R)-2- cyclohexyl-1-((S)-1-ethoxycarbonyl-2-methyl-propylcarbamoyl)-ethyl]-ureido}- hexansäure, (S)-6-Amino-2-{3-[(R)-2-cyclohexyl-1 -((S)-1 -ethoxycarbonyl-2- phenyl-ethylcarbamoyl)-ethyl]-ureido}-hexansäure, (S)-6-Amino-2-(3-{(R)-2- cyclohexyl-1-[(thiophen-2-ylmethyl)-carbamoyl]-ethyl}-ureido)-hexansäure, (S)- 6-Amino-2-[3-((R)-2-cyclohexyl-1 -cyclopropylcarbamoyl-ethyO-ureido]- hexansäure, (S)-6-Amino-2-{3-[(R)-2-cyclohexyl-1 -((R)-1 ,2-dimethyl- propylcarbamoyl)-ethyl]-ureido}-hexansäure, (S)-6-Amino-2-{3-[(R)-2- cyclohexyl-1-(1-ethyl-propylcarbamoyl)-ethyl]-ureido}-hexansäure, (S)-6-Amino- 2-{3-[(R)-1-cyclohexylmethyl-2-(2-methyl-pyrrolidin-1-yl)-2-oxo-ethyl]-ureido}- hexansäure, (S)-6-Amino-2-{3-[(R)-2-cyclohexyl-1 -((S)-1 -cyclohexyl- ethylcarbamoyl)-ethyl]-ureido}-hexansäure, (S)-6-Amino-2-{3-[(R)-2-cyclohexyl- 1 -((1 S,2R)-1 -methoxycarbonyl-2-methyl-butylcarbamoyl)-ethyl]-ureido}- hexansäure, (S)-6-Amino-2-{3-[(R)-5-benzyloxycarbonylamino-1-(4-chlor- benzylcarbamoyl)-pentyl]-ureido}-hexansäure, (S)-6-Amino-2-(3-{(R)-2- cyclohexyl-1-[(thiophen-3-ylmethyl)-carbamoyl3-ethyl}-ureido)-hexansäure, (S)-Amino-2- {3 - [(R) -5-benzyloxycarbonylamino-1 - ((R) -1-methoxycarbonyl-ethylcarbamoyl) -pentyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3 - [(R) -5-benzyloxycarbonylamino-1 - ((R) -1-phenyl-ethylcarbamoyl) -pentyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3 - [(R) - 5-benzyloxycarbonylamino-1- (3-phenyl-propylcarbamoyl) -pentyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3 - [(R) -2-cyclohexyl-1 - ((S) 1-ethoxycarbonyl-2-methyl-propylcarbamoyl) -ethyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3 - [(R) -2-cyclohexyl-1 - ((S) -1 -ethoxycarbonyl-2-phenyl-ethylcarbamoyl) -ethyl] -ureido} -hexanoic acid, (S) -6-amino-2- (3 - {(R) -2-cyclohexyl-1 - [(thiophen-2-ylmethyl) -carbamoyl] -ethyl} -ureido) -hexanoic acid, (S) -6-amino-2- [3 - ((R) -2-cyclohexyl-1-cyclopropylcarbamoyl-ethyl-ureido] -hexanoic acid, (S) -6 -Amino-2- {3 - [(R) -2-cyclohexyl-1 - ((R) -1,2-dimethyl-propylcarbamoyl) -ethyl] -ureido} -hexanoic acid, (S) -6-amino-2 - {3 - [(R) -2-cyclohexyl-1- (1-ethyl-propylcarbamoyl) -ethyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3 - [(R) -1 cyclohexylmethyl-2- (2-methyl-pyrrolidin lidin-1-yl) -2-oxo-ethyl] -ureido} - hexanoic acid, (S) -6-amino-2- {3 - [(R) -2-cyclohexyl-1 - ((S) -1 - cyclohexyl-ethylcarbamoyl) -ethyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3 - [(R) -2-cyclohexyl-1 - ((1S, 2R) -1-methoxycarbonyl-2 -methyl-butylcarbamoyl) -ethyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3 - [(R) -5-benzyloxycarbonylamino-1- (4-chloro-benzylcarbamoyl) -pentyl] -ureido } -hexanoic acid, (S) -6-amino-2- (3 - {(R) -2-cyclohexyl-1 - [(thiophen-3-ylmethyl) -carbamoyl-3-ethyl} -ureido) -hexanoic acid, (S) -
6-Amino-2-(3-{(R)-2-cyclohexyl-1-[(R)-1-(4-fluor-phenyl)-ethylcarbamoyl]-ethyl}- ureido)-hexansäure, (S)-6-Amino-2-{3-[(R)-2-cyclohexyl-1-(1 ,2,3,4-tetrahydro- naphthalen-1-ylcarbamoyl)-ethyl]-ureido}-hexansäure, (S)-6-Amino-2-[3-((R)-2- cyclohexyl-i-propylcarbamoyl-ethyO-ureidoJ-hexansäure, (S)-6-Amino-2-(3-{(R)- 1 -[(biphenyl-2-ylmethyl)-carbamoyl]-2-cyclohexyl-ethyl}-ureido)-hexansäure, (S)-6-Amino-2- (3 - {(R) -2-cyclohexyl-1 - [(R) -1- (4-fluoro-phenyl) -ethylcarbamoyl] -ethyl} -ureido) -hexanoic acid, (S) - 6-Amino-2- {3 - [(R) -2-cyclohexyl-1- (1,2,3,4-tetrahydronaphthalene-1-ylcarbamoyl) ethyl] -ureido} -hexanoic acid, (S) - 6-Amino-2- [3 - ((R) -2-cyclohexyl-i-propylcarbamoyl-ethyl-ureido] -hexanoic acid, (S) -6-amino-2- (3 - {(R) -1 - [( biphenyl-2-ylmethyl) -carbamoyl] -2-cyclohexyl-ethyl} -ureido) -hexanoic acid, (S) -
6-Amino-2-{3-[(R)-2-cyclohexyl-1-((R)-2-phenyl-cyclopropylcarbamoyl)-ethyl]- ureidoj-hexansäure, (S)-6-Amino-2-(3-{(R)-2-cyclohexyl-1-[(pyridin-3-ylmethyl)- 1826-Amino-2- {3 - [(R) -2-cyclohexyl-1 - ((R) -2-phenyl-cyclopropylcarbamoyl) -ethyl] -ureido-hexanoic acid, (S) -6-amino-2-one 3 - {(R) -2-cyclohexyl-1 - [(pyridin-3-ylmethyl) - 182
carbamoyl]-ethyl}-ureido)-hexansäure, (S)-6-Amino-2-(3-{(R)-2-cyclohexyl-1- [(pyridin-2-ylmethyl)-carbamoyl]-ethyl}-ureido)-hexansäure, (S)-6-Amino-2-{3- [(R)-2-cyclohexyl-1-(1-methyl-piperidin-4-ylcarbamoyl)-ethyl]-ureido}- hexansäure, (S)-6-Amino-2-{3-[(R)-2-cyclohexyl-1-(3,3,3-trifluor- propylcarbamoyl)-ethyl]-ureido}-hexansäure, (S)-6-Amino-2-{3-[(R)-2- cyclohexyl-1-(2-methyl-butyl-carbamoyl)-ethyl]-ureido}-hexansäure, (S)-6- Amino-2-{3-[(R)-2-cyclohexyl-1-(cyclopropylmethyl-carbamoyl)-ethyl]-ureido}~ hexansäure, (S)-6-Amino-2-{3-[(R)-2-cyclohexyl-1 -(3,5-difluor- benzylcarbamoyl)-ethyl]-ureido}-hexansäure, (S)-6-Amino-2-{3-[(R)-2- cyclohexyl-1-(2,3-dimethyl-cyclohexylcarbamoyl)-ethyl]-ureido}-hexansäure, (S)-carbamoyl] -ethyl} -ureido) -hexanoic acid, (S) -6-amino-2- (3 - {(R) -2-cyclohexyl-1- [(pyridin-2-ylmethyl) -carbamoyl] -ethyl} - ureido) -hexanoic acid, (S) -6-amino-2- {3- [(R) -2-cyclohexyl-1- (1-methyl-piperidin-4-ylcarbamoyl) -ethyl] -ureido} -hexanoic acid, ( S) -6-amino-2- {3 - [(R) -2-cyclohexyl-1- (3,3,3-trifluoropropylcarbamoyl) -ethyl] -ureido} -hexanoic acid, (S) -6-amino -2- {3 - [(R) -2-cyclohexyl-1- (2-methyl-butyl-carbamoyl) -ethyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3 - [( R) -2-cyclohexyl-1- (cyclopropylmethyl-carbamoyl) -ethyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3 - [(R) -2-cyclohexyl-1 - (3, 5-difluoro-benzylcarbamoyl) -ethyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3 - [(R) -2-cyclohexyl-1- (2,3-dimethyl-cyclohexylcarbamoyl) -ethyl ] -ureido} -hexanoic acid, (S) -
6-Amino-2-{3-[(R)-2-cyclohexyl-1-(1 ,2,3,4-tetrahydro-naphthalen-2- ylcarbamoyl)-ethyl]-ureido}-hexansäure, (S)-2-{3-[(R)-1-(Adamantan-2- ylcarbamoyO^-cyclohexyl-ethyll-ureidoJ-δ-amino-hexansäure, (S)-6-Amino-2- {3-[(R)-2-cyclohexyl-1-(1 ,3-dimethyl-butylcarbamoyl)-ethyl]-ureido}-hexansäure, (S)-6-Amino-2-[3-((R)-2-cyclohexyl-1 -isobutylcarbamoyl-ethyl)-ureido]- hexansäure, (S)-6-Amino-2-{3-[(R)-2-cyclohexyl-1 -((S)-1 ,7,7-trimethyl- bicyclo[2.2.1 ]hept-2-ylcarbamoyl)-ethyl]-ureido}-hexansäure, (S)-2-(3-{(R)-1 - [(Adamantan-i-ylmethylJ-carbamoyll^-cyclohexyl-ethy^-ureidoJ-δ-amino- hexansäure, (S)-2-{3-[(R)-1 -(Adamantan-1 -ylcarbamoyl)-2-cyclohexyl-ethyl]- ureido}-6-amino-hexansäure, (S)-6-Amino-2-{3-[(R)-2-cyclohexyl-1 -(1 - methoxycarbonyl-1-methyl-ethylcarbamoyl)-ethyl]-ureido}-hexansäure, S)-6- Amino-2-[3-((R)-2-cyclohexyl-1-cyclohexylcarbamoyl-ethyl)-ureido]-hexansäure, (S)-6-Amino-2-(3-{(R)-2-cyclohexyl-1-[(pyridin-4-ylmethyl)-carbamoyl]-ethyl}- ureido)-hexansäure, 1 -{(R)-2-[3-((S)-5-Amino-1 -carboxy-pentyl)-ureido]-3- cyclohexyl-propionylamino}-cyclopropanecarboxylic acid ethyl ester, (S)-6-6-Amino-2- {3 - [(R) -2-cyclohexyl-1- (1,2,3,4-tetrahydro-naphthalen-2-ylcarbamoyl) -ethyl] -ureido} -hexanoic acid, (S) - 2- {3 - [(R) -1- (adamantan-2-ylcarbamoyl) -cyclohexyl-ethyll-ureido] -Δ-amino-hexanoic acid, (S) -6-amino-2- {3 - [(R) - 2-cyclohexyl-1- (1,3-dimethyl-butylcarbamoyl) -ethyl] -ureido} -hexanoic acid, (S) -6-amino-2- [3 - ((R) -2-cyclohexyl-1-isobutylcarbamoyl) ethyl) -ureido] - hexanoic acid, (S) -6-amino-2- {3 - [(R) -2-cyclohexyl-1 - ((S) -1, 7,7-trimethyl-bicyclo [2.2.1 ] hept-2-ylcarbamoyl) -ethyl] -ureido} -hexanoic acid, (S) -2- (3 - {(R) -1 - [(adamantan-1-ylmethyl-1-carbamoyl) -cyclohexyl-ethyl-ureido] δ-amino-hexanoic acid, (S) -2- {3 - [(R) -1- (adamantane-1-ylcarbamoyl) -2-cyclohexyl-ethyl] -ureido} -6-amino-hexanoic acid, (S) - 6-Amino-2- {3 - [(R) -2-cyclohexyl-1- (1-methoxycarbonyl-1-methyl-ethylcarbamoyl) -ethyl] -ureido} -hexanoic acid, S) -6-amino-2- [ 3 - ((R) -2-cyclohexyl-1-cyclohexylcarbamoyl-ethyl) -ureido] -hexanoic acid, (S) -6-amino-2- (3 - {(R) -2-cyclohexyl-1 - [(pyridine 4-ylmethyl) -carbamoyl] -ethyl} -ureido) -hexanoic acid, 1 - {(R) -2- [3 - ((S) -5-amino-1-carboxypentyl) -ureido] -3-cyclohexyl-propionylamino} -cyclopropanecarboxylic acid ethyl ester, (S) -6-
Amino-2-(3-{(R)-2-cyclohexyl-1-[((1S,2S)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3- ylmethyl)-carbamoyl]-ethyl}-ureido)-hexansäure, (S)-6-Amino-2-(3-{(R)-2- cyclohexyl-1 -[(S)-(1 ,2, 3,4-tetrahydro-naphthalen-2-yl)carbamoyl]-ethyl}-ureido)- hexansäure, S)-6-Amino-2-{3-[(R)-1-(4-tert-butyl-cyclohexylcarbamoyl)-2- cyclohexyl-ethyl]-ureido}-hexansäure, (S)-6-Amino-2-[3-((R)-1 -cyclohexylmethyl-Amino-2- (3 - {(R) -2-cyclohexyl-1 - [((1S, 2S) -2,6,6-trimethyl-bicyclo [3.1.1] hept-3-ylmethyl) -carbamoyl] - ethyl} -ureido) -hexanoic acid, (S) -6-amino-2- (3 - {(R) -2-cyclohexyl-1 - [(S) - (1, 2, 3,4-tetrahydro-naphthalene) 2-yl) carbamoyl] -ethyl} -ureido) -hexanoic acid, S) -6-amino-2- {3 - [(R) -1- (4-tert-butyl-cyclohexylcarbamoyl) -2-cyclohexyl-ethyl] -ureido} -hexanoic acid, (S) -6-amino-2- [3 - ((R) -1 -cyclohexylmethyl-
2-oxo-2-pyrrolidin-1-yl-ethyl)-ureido]-hexansäure, 3-(6-Amino-pyridin-3-yl)-2-{3- [(R)-I -(bicyclo[2.2.1 ihept^-ylcarbamoyO^-cyclohexyl-ethylJ-ureido}- 1832-oxo-2-pyrrolidin-1-yl-ethyl) -ureido] -hexanoic acid, 3- (6-amino-pyridin-3-yl) -2- {3- [(R) -I- (bicyclo [2.2 .1 ihept ^ -ylcarbamoyO ^ -cyclohexyl-ethyl-ureido} - 183
propansäure, (S)-6-Amino-2-(3-{(R)-2-cyclohexyl-1 -[(1 -methyl-1 H- benzoimidazol-2-ylmethyl)-carbamoyl]-ethyl}-ureido)-hexansäure, 3-(3-Amino- cyclobutyl)-2-{3-[(R)-1-(bicyclo[2.2.1]hept-2-ylcarbamoyl)-2-cyclohexyl-ethyl]- ureido}-propansäure, (S)-6-Amino-2-{3-[(R)-1 -((1 S,2R)-1 -carbamoyl-2-methyl- butylcarbamoyO^-cyclohexyl-ethyll-ureidoJ-hexansäure, (S)-6-Amino-2-{3-[(R)-propanoic acid, (S) -6-amino-2- (3 - {(R) -2-cyclohexyl-1 - [(1-methyl-1H-benzoimidazol-2-ylmethyl) -carbamoyl] -ethyl} -ureido) hexanoic acid, 3- (3-amino-cyclobutyl) -2- {3 - [(R) -1- (bicyclo [2.2.1] hept-2-ylcarbamoyl) -2-cyclohexyl-ethyl] -ureido} -propanoic acid , (S) -6-Amino-2- {3 - [(R) -1 - ((1S, 2R) -1-carbamoyl-2-methyl-butylcarbamoyl-cyclohexyl-ethyl-ureido-1-hexanoic acid, (S. ) -6-amino-2- {3 - [(R) -
5-benzyloxycarbonylamino-1-((1S,2R)-1-carbamoyl-2-methyl-butylcarbamoyl)- pentyl]-ureido}-hexansäure, (S)-6-Amino-2-[3-((R)-2-cyclohexyl-1 -{(S)-1 -[(S)-2- (4-hydroxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-methyl- propylcarbamoyl}-ethyl)-ureido]-hexansäure, (S)-6-Amino-2-[3-((R)-5- benzyloxycarbonylamino-1 -{(S)-1 -[(S)-2-(1 H-indol-3-yl)-1 -methoxycarbonyl- ethylcarbamoyl]-2-methyl-propylcarb-amoyl}-penty!)-ureido]-hexansäure, (S)-6- Amino-2-(3-{(R)-1 -[1-((S)-I -benzyl-2-hydroxy-ethylcarbamoyl)-2-methyl- propylcarbamoylj^-cyclohexyl-ethy^-ureidoj-hexansäure, (S)-6-Amino-2-(3- {(R)-1 -[(1 S,2R)-1 -((S)-1 -carboxy-2-phenyl-ethylcarbamoyl)-2-methyl- butylcarbamoyπ^-cyclohexyl-ethy^-ureidoj-hexansäure, (S)-6-Amino-2-(3-{(R)-5-benzyloxycarbonylamino-1 - ((1S, 2R) -1-carbamoyl-2-methylbutylcarbamoyl) -pentyl] -ureido} -hexanoic acid, (S) -6-amino-2- [3 - ((R) - 2-cyclohexyl-1 - {(S) -1 - [(S) -2- (4-hydroxy-phenyl) -1-methoxycarbonyl-ethylcarbamoyl] -2-methyl-propylcarbamoyl} -ethyl) -ureido] -hexanoic acid, (S) -6-Amino-2- [3 - ((R) -5-benzyloxycarbonylamino-1 - {(S) -1 - [(S) -2- (1H-indol-3-yl) -1 -methoxycarbonyl-ethylcarbamoyl] -2-methyl-propylcarbamoyl} -penty!) - ureido] -hexanoic acid, (S) -6-amino-2- (3 - {(R) -1 - [1 - ((S. ) -I-benzyl-2-hydroxy-ethylcarbamoyl) -2-methyl-propylcarbamoyl-cyclohexyl-ethyl-ureido-hexanoic acid, (S) -6-amino-2- (3- {(R) -1 - [ (1S, 2R) -1 - ((S) -1-carboxy-2-phenyl-ethylcarbamoyl) -2-methyl-butylcarbamoyl-cyclohexyl-ethyl-ureido-hexanoic acid, (S) -6-amino-2 - (3 - {(R) -
1-[(S)-1-((S)-1-carbamoyl-2-methyl-propylcarbamoyl)-2-methyl- propylcarbamoyl^-cyclohexyl-ethylj-ureidoj-hexansäure, (S)-2-{3-[(R)-5- Benzyloxycarbonylamino-1 -((1 S,2R)-1 -carbamoyl-2-methyl-butylcarbamoyl)- pentyl]-ureido}-5-guanidino-pentan-säure, (S)-2-(3-{(R)-5- Benzyloxycarbonylamino-1 -[1 -(1 -carbamoyl-2-methyl-propylcarbamoyl)-2- methyl-propylcarbamoyl]-pentyl}-ureido)-5-guanidino-pentansäure, (S)-6-Amino- 2-(3-{(R)-5-benzyloxycarbonylamino-1 -[(S)-1 -((S)-1 -carbamoyl-2-methyl- propylcarbamoyl)-2-methyl-propylcarbamoyl]-pentyl}-ureido)-hexansäure, (S)-6- Amino-2-(3-{(R)-5-benzyloxycarbonylamino-1 -[(1 S,2R)-1 -((S)-1 -carboxy-2- phenyl-ethylcarbamoyl)-2-methyl-butylcarb-amoyl]-pentyl}-ureido)-hexansäure,1 - [(S) -1 - ((S) -1-carbamoyl-2-methyl-propylcarbamoyl) -2-methyl-propylcarbamoyl-cyclohexyl-ethylj-ureidoj-hexanoic acid, (S) -2- {3- [ (R) -5-benzyloxycarbonylamino-1 - ((1S, 2R) -1-carbamoyl-2-methylbutylcarbamoyl) -pentyl] -ureido} -5-guanidino-pentanoic acid, (S) -2- ( 3 - {(R) -5-Benzyloxycarbonylamino-1 - [1- (1-carbamoyl-2-methyl-propylcarbamoyl) -2-methyl-propylcarbamoyl] -pentyl} -ureido) -5-guanidino-pentanoic acid, (S) 6-amino-2- (3 - {(R) -5-benzyloxycarbonylamino-1 - [(S) -1 - ((S) -1-carbamoyl-2-methyl-propylcarbamoyl) -2-methyl-propylcarbamoyl] -pentyl} -ureido) -hexanoic acid, (S) -6-amino-2- (3 - {(R) -5-benzyloxycarbonylamino-1 - [(1S, 2R) -1 - ((S) -1 - carboxy-2-phenyl-ethylcarbamoyl) -2-methylbutylcarbamoyl] -pentyl} -ureido) -hexanoic acid,
(S)-6-Amino-2-{3-[(R)-5-benzyloxy-carbonylamino-1-((R)-1-carbamoyl-2-methyl- butylcarbamoyl)-pentyl]-ureido}-hexansäure, 2-{(S)-3-[(R)-2-Cyclohexyl-1- ((1 R,2S,4R)-1 ,7,7-trimethyl-bicyclo[2.2.1 ]hept-2-ylcarbamoyl)-ethyl]-ureido}-5- guanidino-pentansäure, (S)-6-Amino-2-{3-[(R)-2-cyclohexyl-1-(decahydro- naphthalen-2-ylcarbamoyl)-ethyl]-ureido}-hexansäure, (S)-3-(6-Amino-pyridin-3- yl)-2-{3-[(R)-2-cyclohexyl-1-((1 R,2S,4R)-1 I7,7-trimethyl-bicyclo[2.2.1]hept-2- ylcarbamoyl)-ethyl]-ureido}-propionsäure, (R)-3-(6-Amino-pyridin-3-yl)-2-{3-[(R)- 184(S) -6-amino-2- {3 - [(R) -5-benzyloxycarbonylamino-1 - ((R) -1-carbamoyl-2-methyl-butylcarbamoyl) -pentyl] -ureido} -hexanoic acid; 2 - {(S) -3 - [(R) -2-Cyclohexyl-1- ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-ylcarbamoyl) -ethyl] -ureido} -5-guanidino-pentanoic acid, (S) -6-amino-2- {3 - [(R) -2-cyclohexyl-1- (decahydronaphthalen-2-ylcarbamoyl) -ethyl] - ureido} hexanoic acid, (S) -3- (6-aminopyridin-3-yl) -2- {3 - [(R) -2-cyclohexyl-1 - ((1R, 2S, 4R) -1 I 7,7-trimethyl-bicyclo [2.2.1] hept-2-ylcarbamoyl) -ethyl] -ureido} -propionic acid, (R) -3- (6-aminopyridin-3-yl) -2- {3 - [(R) - 184
2-cyclohexyl-1-((1 R,2S,4R)-1 ,7,7-trimethyl-bicyclo[2.2.1]hept-2-ylcarbamoyl)- ethyl]-ureido}-propionsäure, (S)-5-Amino-2-(3-{2-cyclohexyl-1 -[((1 R,2S,4R)- I JJ-trimethyl-bicyclo^^.iJhept^-ylcarbamoyO-methyll-ethylJ-ureido)- pentansäure, 6-Amino-2-{3-[(R)-2-phenyl-1 -((1 R,2S,4R)-1 ,7,7-tιϊmethyl- bicyclo[2.2.1 ]hept-2-ylcarbamoyl)-ethyl]-ureido}-hexansäure, 6-Amino-2-{3-[2- methyl-1-((R)-(1 R,2S,4R)-1 ,7,7-trimethyl-bicyclo[2.2.1]hept-2-ylcarbamoyl)- propyl]-ureido}-hexansäure, 6-Amino-2-{3-[(R)-cyclohexyl-((1 R,2S,4R)-1 ,7,7- trimethyl-bicyclo[2.2.1 ]hept-2-ylcarbamoyl)-methyl]-ureido}-hexansäure, 6- Amino-2-{3-[3-methyl-1 -((R)-(I R,2S,4R)-1 ,7,7-trimethyl-bicyclo[2.2.1]hept-2- ylcarbamoyl)-butyl]-ureido}-hexansäure, 3-(3-Amino-cyclobutyl)-2-{3-[(R)-1-2-cyclohexyl-1 - ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-ylcarbamoyl) ethyl] -ureido} -propionic acid, (S) -5 -Amino-2- (3- {2-cyclohexyl-1 - [((1R, 2S, 4R) -I-J-trimethyl-bicyclo) -I-heptyl-carbamoyl-O-methyl-ethyl-1-ureido) -pentanoic acid, 6 -Amino-2- {3 - [(R) -2-phenyl-1 - ((1R, 2S, 4R) -1, 7,7-t-methylmicyclo [2.2.1] hept-2-ylcarbamoyl) ethyl] -urido} -hexanoic acid, 6-amino-2- {3- [2-methyl-1 - ((R) - (1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2. 1] hept-2-ylcarbamoyl) propyl] ureido} hexanoic acid, 6-amino-2- {3 - [(R) -cyclohexyl- ((1R, 2S, 4R) -1, 7,7-trimethyl -bicyclo [2.2.1] hept-2-ylcarbamoyl) -methyl] -ureido} -hexanoic acid, 6-amino-2- {3- [3-methyl-1 - ((R) - (IR, 2S, 4R) -1,7,7-trimethyl-bicyclo [2.2.1] hept-2-ylcarbamoyl) -butyl] -ureido} -hexanoic acid, 3- (3-amino-cyclobutyl) -2- {3 - [(R) - 1-
(bicyclo[2.2.1]-hept-2-ylcarbamoyl)-2-cyclohexyl-ethyl]-ureido}-propionsäure Trifluoracetat, 6-Amino-2-{3-[((1 R,2S,4R)-1 ,7,7-trimethyl-bicyclo[2.2.1]hept-2- ylcarbamoyl)-methyl]-ureido}-hexansäure, 6-Amino-2-{3-[1 -methyl-1 - ((1R,2S,4R)-1 ,7,7-trimethyl-bicyclo[2.2.1]hept-2-ylcarbamoyl)-ethyl]-ureido}- hexansäure, 6-Amino-2-{3-[1 -((R)-(I R,2S,4R)-1 , 7,7-trimethyl-bicyclo[2.2.1]- hept-2-ylcarbamoyl)-butyl]-ureido}-hexansäure, (S)-6-Amino-2-{3-[(S)-2- cyclohexyl-1-(3-methyl-cyclohexylcarbamoyl)-ethyl]-ureido}-hexansäure, (S)-6- Amino-2-{3-[(S)-1-(4-tert-butyl-cyclohexylcarbamoyl)-2-cyclohexyl-ethyl]-ureido}- hexan-säure, (S)-6-Amino-2-{3-[(S)-2-cyclohexyl-1-(3,3,5-trimethyl- cyclohexylcarb-amoyl)-ethyl]-ureido}-hexansäure, (S)-4-Guanidino-oxy-2-{3-(bicyclo [2.2.1] -hept-2-ylcarbamoyl) -2-cyclohexyl-ethyl] -ureido} -propionic acid trifluoroacetate, 6-amino-2- {3 - [((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-ylcarbamoyl) -methyl] -ureido} -hexanoic acid, 6-amino-2- {3- [1-methyl-1 - ((1R, 2S, 4R ) -1,7,7-trimethyl-bicyclo [2.2.1] hept-2-ylcarbamoyl) -ethyl] -ureido} -hexanoic acid, 6-amino-2- {3- [1- ((R) - (IR , 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] -hept-2-ylcarbamoyl) -butyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3- [ (S) -2-cyclohexyl-1- (3-methyl-cyclohexylcarbamoyl) -ethyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3 - [(S) -1- (4-tert -butyl-cyclohexylcarbamoyl) -2-cyclohexyl-ethyl] -ureido} -hexanoic acid, (S) -6-amino-2- {3 - [(S) -2-cyclohexyl-1- (3,3,5 -trimethylcyclohexylcarbamoyl) -ethyl] -ureido} -hexanoic acid, (S) -4-guanidino-oxy-2- {3-
[(R)-2-cyclohexyl-1-((1 R,2S)-1 ,7,7-trimethyl-bicyclo[2.2.1]hept-2-ylcarbamoyl)- ethyl]-ureido}-butansäure, 6-Amino-2-{3-[(R)-2-cyclopropyl-1-((1 R,2S,4R)-1 ,7,7- trimethyl-bicyclo[2.2.1 ]hept-2-ylcarbamoyl)-ethyl]-ureido}-hexansäure, 6-Amino- 2-{3-[(R)-2-cyclobutyl-1 -((1 R,2S,4R)-1 ,7,7-trimethyl-bicyclo[2.2.1 ]hept-2-ylcarb- amoyl)-ethyl]-ureido}-hexansäure, 3-(6-Amino-pyridin-3-yl)-2-{3-[(R)-2- cyclohexyl-1 -((1 R,2S,4R)-1 ,7,7-trimethyl-bicyclo[2.2.1 ]hept-2-ylcarbamoyl)- ethyl]-ureido}-propionsäure, 6-Amino-2-{3-[2-cyclopentyl-1-((1R,2S,4R)-1 ,7,7- trimethyl-bicyclo[2.2.1 ]hept-2-ylcarbamoyl)-ethyl]-ureido}-hexansäure, (S)-6- Amino-2-{3-[(R)-5-benzyloxycarbonylamino-1-((R)-1-methoxycarbonyl- ethylcarbamoyl)-pentyl]-ureido}-hexansäure, (S)-6-Amino-2-(3-{(R)-5- benzyloxycarbonylamino-1-[(S)-2-methyl-1-(3-phenyl-propylcarbamoyl)- propylcarbamoyl]-pentyl}-ureido)-hexansäure, (S)-6-Amino-2-(3-{(R)-5- 185[(R) -2-cyclohexyl-1 - ((1R, 2S) -1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-ylcarbamoyl) -ethyl] -ureido} -butanoic acid, Amino-2- {3 - [(R) -2-cyclopropyl-1 - ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-ylcarbamoyl) -ethyl ] -ureido} hexanoic acid, 6-amino-2- {3 - [(R) -2-cyclobutyl-1 - ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1 ] hept-2-ylcarbamoyl) -ethyl] -ureido} -hexanoic acid, 3- (6-amino-pyridin-3-yl) -2- {3 - [(R) -2-cyclohexyl-1 - (( 1 R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-ylcarbamoyl) ethyl] -ureido} -propionic acid, 6-amino-2- {3- [2-cyclopentyl -1 - ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-ylcarbamoyl) -ethyl] -ureido} -hexanoic acid, (S) -6-amino-2 - {3 - [(R) -5-benzyloxycarbonylamino-1 - ((R) -1-methoxycarbonyl-ethylcarbamoyl) -pentyl] -ureido} -hexanoic acid, (S) -6-amino-2- (3 - {( R) -5-benzyloxycarbonylamino-1 - [(S) -2-methyl-1- (3-phenyl-propylcarbamoyl) -propylcarbamoyl] -pentyl} -ureido) -hexanoic acid, (S) -6-amino-2- ( 3 - {(R) -5- 185
benzyloxycarbonylamino-1 -[(S)-1 -((1 R,2R,4S)-bicyclo[2.2.1 ]hept-2-ylcarb- amoyl)-2-methyl-propylcarbamoyl]-pentyl}-ureido)-hexansäure, (S)-6-Amino-2- (3-{(R)-5-benzyloxycarbonyl-amino-1-[(S)-1-((1S,4R)-bicyclo[2.2.1]hept-2- ylcarbamoyl)-2-methyl-propylcarbamoyl]-pentyl}-ureido)-hexansäure, (S)-6- Amino-2-{3-[(R)-5-benzyloxycarbonylamino-1 -((S)-1 -cyclopropylcarbamoyl-2- methyl-propylcarbamoyl)-pentyl]-ureido}-hexansäure, (S)-6-Amino-2-(3-{(R)-5- benzyloxycarbonylamino-1 -[(S)-1 -((S)-1 -ethoxycarbonyl-2-phenyl-ethylcarb- amoyl)-2-methyl-propylcarbamoyl]-pentyl}-ureido)-hexansäure, (S)-6-Amino-2- (3-{(R)-5-benzyloxycarbonyIamino-1 -[(S)-1 -((S)-1 -ethoxycarbonyl-2-methyl- propylcarbamoyl)-2-methyl-propylcarbamoyl]-pentyl}-ureido)-hexansäure, (S)-6-benzyloxycarbonylamino-1 - [(S) -1 - ((1R, 2R, 4S) -bicyclo [2.2.1] hept-2-ylcarbamoyl) -2-methyl-propylcarbamoyl] -pentyl} -ureido) -hexanoic acid , (S) -6-Amino-2- (3 - {(R) -5-benzyloxycarbonyl-amino-1 - [(S) -1 - ((1S, 4R) -bicyclo [2.2.1] hept-2 - ylcarbamoyl) -2-methyl-propylcarbamoyl] -pentyl} -ureido) -hexanoic acid, (S) -6-amino-2- {3 - [(R) -5-benzyloxycarbonylamino-1 - ((S) -1 - cyclopropylcarbamoyl-2-methyl-propylcarbamoyl) -pentyl] -ureido} -hexanoic acid, (S) -6-amino-2- (3 - {(R) -5-benzyloxycarbonylamino-1 - [(S) -1 - (( S) -1-ethoxycarbonyl-2-phenyl-ethylcarbamoyl) -2-methyl-propylcarbamoyl] -pentyl} -ureido) -hexanoic acid, (S) -6-amino-2- (3 - {(R) -5 -benzyloxycarbonyl-amino-1 - [(S) -1 - ((S) -1-ethoxycarbonyl-2-methyl-propylcarbamoyl) -2-methyl-propylcarbamoyl] -pentyl} -ureido) -hexanoic acid, (S) -6-
Amino-2-[3-((R)-5-benzyloxycarbonylamino-1 -{(S)-1 -[(S)-1 -(4-chloro-phenyl)- ethylcarbamoyl]-2-methyl-propylcarbamoyl}-pentyl)-ureido]-hexan-säure, (S)-6- Amino-2-(3-{(R)-5-benzyloxycarbonylamino-1-[(S)-2-methyl-1-(3-methyl- cyclohexylcarbamoyl)-propylcarbamoyl]-pentyl}-ureido)-hexansäure, (S)-Q- Amino-2-(3-{(R)-5-benzyloxycarbonylamino-1 -[(S)-1 -(2,2-dimethyl- propylcarbamoyl)-2-methyl-propylcarbamoyl]-pentyl}-ureido)-hexansäure, (S)-6- Amino-2-(3-{(R)-5-benzyloxycarbonylamino-1 -[(S)-2-methyl-1 -((R)-1 -phenyl- ethylcarbamoyl)-propylcarbamoyl]-pentyl}-ureido)-hexansäure, (S)-5-Amino-2- {3-[(R)-2-cyclohexyl-1-(3-methyl-butylcarbamoyl)-ethyl]-ureido}-pentansäure Hydochlorid, (S)-5-Amino-2-{3-[(R)-2-cyclohexyl-1-((1 R,2S,4R)-1 ,7,7-tri-methyl- bicyclo[2.2.1 ]hept-2-ylcarbamoyl)-ethyl]-ureido}-pentansäure, (S)-6-Amino-2-(3- {(R)-5-benzyloxycarbonylamino-1 -[(S)-1 -((S)-1 -cyclohexyl-ethylcarbamoyl)-2- methyl-propylcarbamoyl]-pentyl}-ureido)-hexansäure, (S)-6-Amino-2-(3-{(R)-5- benzyloxycarbonylamino-1 -[(S)-2-methyl-1 -(1 ,2,2-trimethyl-propylcarbamoyl)- propylcarbamoyl]-pentyl}-ureido)-hexansäure, (S)-6-Amino-2-(3-{(R)-5- benzyloxycarbonylamino-1 -[(S)-2-methyl-1 -((1 R,2S)-2-phenyl- cyclopropylcarbamoyl)-propylcarbamoyl]-pentyl}-ureido)-hexansäure, (S)-6- Amino-2-(3-{(R)-5-benzyloxycarbonylamino-1-[(S)-2-methyl-1-(2-methyl- cyclohexylcarbamoyl)-propylcarbamoyl]-pentyl}-ureido)-hexansäure, (S)-6- Amino-2-(3-{(R)-5-benzyloxycarbonylamino-1 -[(S)-1 -(4-chloro-benzylcarb- amoyl)-2-methyl-propylcarbamoyl]-pentyl}-ureido)-hexansäure, (S)-6-Amino-2- {3-[(R)-5-benzyloxycarbonylamino-1 -((S)-1 -carbamoyl-2-methyl- 186Amino-2- [3 - ((R) -5-benzyloxycarbonylamino-1 - {(S) -1 - [(S) -1- (4-chloro-phenyl) -ethylcarbamoyl] -2-methyl-propylcarbamoyl} - pentyl) ureido] hexanoic acid, (S) -6-amino-2- (3 - {(R) -5-benzyloxycarbonylamino-1 - [(S) -2-methyl-1- (3-methyl) cyclohexylcarbamoyl) -propylcarbamoyl] -pentyl} -ureido) -hexanoic acid, (S) -Q-amino-2- (3 - {(R) -5-benzyloxycarbonylamino-1 - [(S) -1 - (2,2-) dimethyl-propylcarbamoyl) -2-methyl-propylcarbamoyl] -pentyl} -ureido) -hexanoic acid, (S) -6-amino-2- (3 - {(R) -5-benzyloxycarbonylamino-1 - [(S) -2 -methyl-1 - ((R) -1-phenyl-ethylcarbamoyl) -propylcarbamoyl] -pentyl} -ureido) -hexanoic acid, (S) -5-amino-2- {3 - [(R) -2-cyclohexyl- 1- (3-methyl-butylcarbamoyl) -ethyl] -ureido} -pentanoic acid hydrofluoride, (S) -5-amino-2- {3 - [(R) -2-cyclohexyl-1 - ((1 R, 2 S, 4R) -1,7,7-tri-methyl-bicyclo [2.2.1] hept-2-ylcarbamoyl) -ethyl] -ureido} -pentanoic acid, (S) -6-amino-2- (3- {(R ) -5-benzyloxycarbonylamino-1 - [(S) -1 - ((S) -1-cyclohexyl-ethylcarbamoyl) -2-methyl-propylcarbamoyl] -pentyl} -ureido) -hexanoic acid, (S) -6-amino- 2- (3 - {(R) -5- benzyloxycarbonylamino-1 - [(S) -2-methyl-1- (1,2,2-trimethyl-propylcarbamoyl) -propylcarbamoyl] -pentyl} -ureido) -hexanoic acid, (S) -6-amino-2- (3 - {(R) -5-benzyloxycarbonylamino-1 - [(S) -2-methyl-1 - ((1R, 2S) -2-phenyl-cyclopropylcarbamoyl) -propylcarbamoyl] -pentyl} -ureido) -hexanoic acid, ( S) -6-amino-2- (3 - {(R) -5-benzyloxycarbonylamino-1 - [(S) -2-methyl-1- (2-methylcyclohexylcarbamoyl) -propylcarbamoyl] -pentyl} -ureido) hexanoic acid, (S) -6-amino-2- (3 - {(R) -5-benzyloxycarbonylamino-1 - [(S) -1- (4-chlorobenzylcarbamoyl) -2-methyl-propylcarbamoyl] -pentyl} -ureido) -hexanoic acid, (S) -6-amino-2- {3 - [(R) -5-benzyloxycarbonylamino-1 - ((S) -1-carbamoyl-2-methyl] 186
propylcarbamoyl)-pentyl]-ureido}-hexansäure, (R)-3-(2-Amino-ethansulfonyl)-2- {3-[(R)-2-cyclohexyl-1-((1 R, 2S, 4R)-1 ,7,7-trimethyl-bicyclo[2.2.1]hept-2- ylcarbamoyl)-ethyl]-ureido}propionsäure oder (R)-3-(2-Amino-ethylsulfanyl)-2-{3- [(R)-2-cyclohexyl-1-((1R, 2S, 4R)-1 ,7,7-trimethyl-bicyclo[2.2.1]hept-2- 5 ylcarbamoyl)-ethyl]-ureido}propionsäure ist.propylcarbamoyl) -pentyl] -ureido} -hexanoic acid, (R) -3- (2-aminoethanesulfonyl) -2- {3 - [(R) -2-cyclohexyl-1 - ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-ylcarbamoyl) -ethyl] -ureido} propionic acid or (R) -3- (2-amino-ethylsulfanyl) -2- {3- [( R) is -2-cyclohexyl-1 - ((1R, 2S, 4R) -1, 7,7-trimethyl-bicyclo [2.2.1] hept-2-ylcarbamoyl) -ethyl] -ureido} propionic acid.
21. Verfahren zur Herstellung der Verbindung der Formel I gemäß einem oder mehreren der Ansprüche 11 bis 20, dadurch gekennzeichnet, dass man a) eine Verbindung der Formel Il21. A process for the preparation of the compound of the formula I according to one or more of claims 11 to 20, characterized in that a) a compound of the formula II
OO
I O R 2 wobei R2 und PG die in der Verbindung der Formel I genannten Bedeutungen haben, mit einem Phosgenäquivalent wie Carbonyldiimidazol, Diphosgen, Triphosgen oder Phosgen zu einer Zwischenverbindung der Formel IM umsetzt,Wherein R 2 and PG have the meanings given in the compound of the formula I, with a phosgene equivalent such as carbonyldiimidazole, diphosgene, triphosgene or phosgene to form an intermediate compound of the formula III,
Figure imgf000188_0001
5 wobei R2, R9 und PG die in der Verbindung der Formel I genannten
Figure imgf000188_0001
Wherein R 2, R 9 and PG are those mentioned in the compound of formula I.
Bedeutungen haben, und die Verbindung der Formel III mit einer Aminosäure der Formel IV,Have meanings, and the compound of the formula III with an amino acid of the formula IV,
Figure imgf000188_0002
wobei R3 und R7 die in der Verbindung der Formel I genannte Bedeutung 0 haben, zu einer Verbindung der Formel V umsetzt,
Figure imgf000188_0002
where R 3 and R 7 have the meaning 0 in the compound of the formula I, to give a compound of the formula V,
Figure imgf000188_0003
wobei R2, R3, R7, R9 und PG die in der Verbindung der Formel I genannten Bedeutungen haben, anschließend wird die Verbindung der Formel V mit einem 187
Figure imgf000188_0003
where R 2, R 3, R 7, R 9 and PG have the meanings given in the compound of the formula I, then the compound of the formula V with a 187
Amin der Formel NH(R6)2Wobei R6 die in der Verbindung der Formel I genannte Bedeutung hat, zu einer Verbindung der Formel VI umgesetztAmine of the formula NH (R6) 2We R6 has the meaning mentioned in the compound of formula I, converted to a compound of formula VI
Figure imgf000189_0001
wobei R2, R3, R4, R7, R9 und PG die in der Verbindung der Formel I genannten Bedeutungen haben, und dann in eine Verbindung der Formel I überführt, oder b) eine Verbindung der Formel Il wird mit einer Verbindung der Formel IX,
Figure imgf000189_0001
where R 2, R 3, R 4, R 7, R 9 and PG have the meanings given in the compound of the formula I, and then converted into a compound of the formula I, or b) a compound of the formula II is reacted with a compound of the formula IX,
Figure imgf000189_0002
wobei R3, R4, R7 und PG die in der Verbindung der Formel I genannten Bedeutungen haben, zu einer Verbindung der Formel X umgesetzt,
Figure imgf000189_0002
where R 3, R 4, R 7 and PG have the meanings given in the compound of the formula I, to give a compound of the formula X,
Figure imgf000189_0003
wobei R2, R3, R4, R7, R9 und PG die in der Verbindung der Formel I genannten Bedeutungen haben, und dann in eine Verbindung der Formel I überführt, oder c) eine nach den Verfahren a) oder b) hergestellte Verbindung der Formel I, oder eine geeignete Vorstufe der Formel I1 die aufgrund ihrer chemischen Struktur in enantiomeren Formen auftritt, durch Salzbildung mit enantiomerenreinen Säuren oder Basen, Chromatographie an chiralen Stationärphasen oder Derivatisierung mittels chiraler enantiomerenreinen Verbindungen wie Aminosäuren, Trennung der somit erhaltenen
Figure imgf000189_0003
where R 2, R 3, R 4, R 7, R 9 and PG have the meanings given in the compound of the formula I, and then converted into a compound of the formula I, or c) a compound of the formula I prepared according to the process a) or b) , or a suitable precursor of the formula I 1 which occurs in enantiomeric forms due to their chemical structure, by salt formation with enantiomerically pure acids or bases, chromatography on stationary chiral phases or derivatization by means of chiral enantiomerically pure compounds such as amino acids, separation of the thus obtained
Diastereomeren, und Abspaltung der chiralen Hilfsgruppen in die reinen Enantiomeren auftrennt, oder d) die nach den Verfahren a) b) oder c) hergestellte Verbindung der Formel I entweder in freier Form isoliert oder im Falle des Vorliegens von sauren oder basischen Gruppen in physiologisch verträgliche Salze umwandelt. 188D) the compounds of the formula I prepared according to the methods a) b) or c) are isolated either in free form or in the case of the presence of acidic or basic groups in physiologically compatible Salts converted. 188
22. Arzneimittel, gekennzeichnet durch einen wirksamen Gehalt an mindestens einer Verbindung der Formel I gemäß einem oder mehreren der Ansprüche 11 bis 20 zusammen mit einem pharmazeutisch geeigneten und physiologisch verträglichen Trägerstoff, Zusatzstoff und/oder anderen Wirk- und Hilfsstoffen. 22. Medicaments, characterized by an effective content of at least one compound of the formula I according to one or more of claims 11 to 20 together with a pharmaceutically suitable and physiologically acceptable carrier, additive and / or other active ingredients and excipients.
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US8580777B2 (en) 2008-06-06 2013-11-12 Sanofi Macrocyclic urea and sulfamide derivatives as inhibitors of TAFIa
US8722655B2 (en) 2008-06-06 2014-05-13 Sanofi Macrocyclic urea and sulfamide derivatives as inhibitors of tafia
US9126955B2 (en) 2008-06-06 2015-09-08 Sanofi Macrocyclic urea and sulfamide derivatives as inhibitors of TAFIa
US9309207B2 (en) 2008-06-06 2016-04-12 Sanofi Macrocyclic urea and sulfamide derivatives as inhibitors of TAFIa
US9688645B2 (en) 2008-06-06 2017-06-27 Sanofi Macrocyclic urea and sulfamide derivatives as inhibitors of TAFIa
US8119673B2 (en) 2008-06-23 2012-02-21 Astrazeneca Ab Compounds 148
US8354444B2 (en) 2008-09-18 2013-01-15 Hoffmann-La Roche Inc. Substituted pyrrolidine-2-carboxamides
WO2010050525A1 (en) 2008-10-29 2010-05-06 大正製薬株式会社 Compound having tafia inhibitory activity
CN105263928A (en) * 2013-06-10 2016-01-20 赛诺菲 Macrocyclic urea derivatives as inhibitors of tafia, their preparation and their use as pharmaceuticals
US9834527B2 (en) 2013-06-10 2017-12-05 Sanofi Macrocyclic urea derivatives as inhibitors of TAFIa, their preparation and their use as pharmaceuticals

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US20100035930A1 (en) 2010-02-11
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